Pediatric intestinal transplantation: Historical notes, principles and controversies

Pediatric intestinal transplantation:Historical notes, principles and controversies

Reyes J, Mazariegos GV, Bond GMD, Green M, Dvorchik I, Kosmach-Park B, Abu-Elmagd K. Pediatric intestinal transplantation: historicalnotes, principles and controversies.Pediatr Transplantation 2002: 6: 193–207. # 2002 Blackwell Munksgaard

Abstract. The development in technique and immunosuppressivemanagement of the last 12 yr have made intestinal transplantation aneffective treatment for children with intestinal failure. The informationprovided in this review support such a conclusion, but was more clearlyvalidated by the March 2001 Medicare Report which provided a nationalcoverage decision of the Social Security Act for intestinal transplantation.As of May 2001, there were 55 centers world-wide which have performed696 intestinal transplants in 656 patients. (Intestinal Transplant Registry,http://www.lhsc.on.ca/itr) the majority of recipients have been children,and there has been a greater need for liver replacement in conjunctionwith the allograft intestine because of a higher incidence of TPN-inducedcholestatic liver disease in children. Though overall long-term survival isapproximately 50%, similar advances in surgical, clinical and immuno-suppressive management since 1995 have improved patient survival tomore than 70% in most experienced programs. Over 80% of survivors areenjoying nutrition-supporting intestinal function. The major causes ofgraft loss and patient demise continues to be rejection and infection.Tacrolimus remains the mainstay of immunosuppressive therapy.Further experience other induction protocols utilizing rapamycin anddaclizumab, as well graft pretreatment protocols may further enhanceresults in the future.

Jorge Reyes, George V. Mazariegos,Geoffrey M.D. Bond, Michael Green,Igor Dvorchik, Beverly Kosmach-Park and Kareem Abu-ElmagdThe Children’s Hospital of Pittsburgh, University ofPittsburgh, Thomas E. Starzl TransplantationInstitute, Pittsburgh, Pennsylvania, USA

Key words: intestinal failure – intestine

transplant – liver intestine transplant –

multivisceral transplant – short gut syndrome

Jorge Reyes MD, Director Pediatric Transplant

Surgery, Children’s Hospital of Pittsburgh, 3705 Fifth

Avenue 4 A/470, Pittsburgh, PA 15213, USA.

Tel.: (412) 692 7867

Fax: (412) 692 6116

E-mail: [email protected]

Accepted for publication 14 January 2002

The close of the 20th century witnessed rapiddevelopments in the field of transplantation.Within 16 years of Medawar’s 1944 (1) demon-stration that disruption of the alloactivated T-cell response could result in the prolongation ofallograft survival, clinical trials of organtransplantation had achieved transplantationof the kidney (2), liver (3), heart (4), lung (5),and pancreas (6). Clinical success with theintestine, however, remained elusive. The les-sons learned over the previous three decadeshave fostered principles which are applicable tothe transplantation of all organs. Successfulshort and long-term survival is dependent onsurgical technique, preservation technology,

adequate immunosuppression, and the eventualinduction of varying degrees of donor specificnon-reactivity.

The experimental canine intestinal modelsdeveloped by Lillehei (who studied both auto-grafts and allografts) (7) in 1959, and Starzl in1960 (who studied the transplantation of thesmall intestine as part of a multivisceral graft)(8), established technical and immunologicobservations on intestinal allografts whichprompted the largely unsuccessful attempts atclinical intestinal transplantation after 1964 (9).As with other solid organs, immunosuppressionwas dogmatic, initially under azathioprine/steroid immunosuppression and then subse-

History of Pediatric Organ Transplantation

Pediatr Transplantation 2002: 6: 193–207

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Pediatric TransplantationISSN 1397-3142

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quently using cyclosporine/steroids. The routinedepletion of graft T-lymphocytes by infusingthe donor with an anti-lymphocyte monoclonalantibody treatment before procurement and byex-vivo irradiation of the intestinal allograftsafter their removal was based on a realizationthat the immunocytes in this lymphoid richorgan could determine transplantation outcome;the fear then was of precipitating graft-vs.-hostdisease (GVHD). Such a strategy was utilized in1987 with the recipient of a multivisceral graft(attempted experimentally in 1960) and whichprovided nutrition-supporting intestinal accom-plished function for 6 months (8, 10).Subsequently, in 1988 by Deltz et al. (11), thetransplantation of an isolated intestinal allo-graft from a live donor, achieving nutritionalfunction for 56 months. Intestine containingcomposite grafts extended the limited survivalof these patients as demonstrated by Grant (12)and later Margreiter (13). The only survivorfrom the cyclosporine era is a cadaveric isolatedintestine recipient performed by Goulet in 1989

(14). Clinical success was principally hamperedbecause of the uncontrollable nature of intest-inal allograft rejection, but peri-operative sur-gical/clinical complications and infection alsoplayed a significant role.

The emergence in 1989 of tacrolimus allowedfor better control of rejection and changed thecourse of clinical intestinal transplantation (15).In doing so, it also helped to demonstrate theinteraction between the immune system of therecipient and the donor immunocytes containedin the transplanted allograft (host-vs.-graft andgraft-vs.-host) (Fig. 1); this has been postulatedas the two-way paradigm of transplantationimmunology (16). Intestinal transplantation isnow feasible and clinically applicable; however,the procedure and post-operative course remaincomplex. In this article the basis for successfulclinical intestinal transplantation will be exam-ined. The intestinal failure population, progresswith surgical technique and the evolution ofimmunosuppressive drug therapy for intestinaltransplantation will be discussed.

Fig. 1. The one way paradigm of both solid organ and bone marrow transplantation assumed a defenseless organ or recipientbeing attacked by a ‘single army’ of immunocytes. The two way paradigm envisages ‘two armies’ of immunocytes (of recipientand donor origin) which under the cloak of immunosuppression will produce varying degrees of non-reactivity.

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What is intestinal organ failure?

Patients who have lost function of their intestinewill not be able to maintain a normal state ofnutrition, fluid and electrolyte balance, or normalgrowth and development. Many diseases canprecipitate this state for varying lengths of timeand include true short gut, as well as functionaldisorders of an anatomically intact gastrointest-inal tract. The introduction of TPN over threedecades ago changed the outcome of countlesschildren who suffered these diseased states. Iteffectively paralleled the temporizing benefits thathemodialysis demonstrated in patients withkidney failure. As survival became better estab-lished, however, it introduced a new set ofmorbidities which were a consequence of thedisease process and its therapy. This host ofmorbidities became known as short gut syn-drome, a broad morphologic diagnosis which ismore an end state of three principal entities:catheter sepsis, paucity of venous access, andTPN induced cholestatic liver disease. Theintestine is not a vital organ; however, its absencewill result in one or a combination of theaforementioned entities. This in turn will produce‘satellite’ complications in other body systems,eventually leading to death. Such patients arereferred to as having ‘intestinal failure’ (IF).

The development of intestinal transplantationhas introduced new approaches to the manage-ment of IF. It has done so by applying multi-disciplinary integrated care to a host of diseaseswhich produce IF in children (17, 18) (Table 1),and defining the criteria for intestinal transplan-tation evaluation (19) which is based on thefollowing:1 Paucity of venous access – ‘accessibility’ for

TPN requires patency of six principal sites: thepairs of internal jugular, subclavian and iliacveins. The use of transhepatic and translumbaraccess is the extreme of venous access loss, andsuch patients are at the end stage of their IF.Although the standards of care for central venous

catheters does not vary significantly in mostcenters in North America and Europe, theevolution of this complication seems almostrandom. Arbitrarily, a loss of 50% of these sitesputs a patient at risk and should prompt referralfor intestinal transplant evaluation.2 Catheter sepsis – as with paucity of venous

access, the frequency, evolution, and severity ofthis complication seems random and is related

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Fig. 2. Probability of survival of 256 patients presenting withintestinal failure. (Reproduced with permission from ref.54).

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Portal fibrosis

Cholestasis

Bridging fibrosisCirrhosis

P = 0.003

Fig. 3. Kaplan–Meir survival curve according tohistopathology liver biopsies in patients with intestinalfailure. (Reproduced with permission from ref. 54).

Table 1. Principal disorders causing intestinal failure in children

Short gut syndrome Intestinal dysmotilityEnterocyte absorptive

impairment Tumors

Congenital malformations Intestinal pseudo-obstruction Microvillus inclusiondisease

Familial polyposis

Necrotizing enterocolitis Intestinal aganglionosis(Hirschsprung’s disease)

Autoimmune or idiopathicenteropathy

Inflammatorypseudo tumor

TraumaVolvulusGastroschisisIntestinal atresia

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not only to appropriateness in catheter care, butalso to the development of resistant bacteria,intestinal bacterial translocation of gut organ-isms, and the loss of immune gut function. Severeinfections can result in metastatic infectious fociand multiple system organ failure (hemodynamicinstability, respiratory and renal failure).3 TPN induced cholestatic liver disease – this

complication seems to be more common inchildren, particularly neonates suffering extensiveloss of their gut. The inception may be dramaticor insidious; it remains the most devastatingcomplication found with IF. The development ofclinical jaundice (bilirubin . 3 mg/dL) warrantsreferral for intestinal transplantation, because itheralds more critical functional manifestations ofliver disease such as coagulopathy, hypoalbumi-nemia, and the development of portal hyperten-sive gastroenteropathy.

Without intestinal transplantation, patientswith IF will die of complications at a dramaticrate, with 1 and 2-yr survivals estimated at 49%and 40%, respectively (20) (Fig. 2). Factorsimpacting the survival of children with IF suggestthat younger patients (,1 yr old) have a higherrisk of dying of IF; these patients usually suffer amassive loss of their intestine and develop liverdisease at an early onset. Children with functionaldisorders will develop complications of IF at alater stage as compared to children who haveanatomic loss of their intestine. The presence orabsence of liver disease and its progression will,however, dictate their short-term survival.Consequently, the functional determinants ofsurvival include the presence of jaundice, hypers-plenism, and coagulopathy.

Morphologically, patients with severe histo-pathologic damage to the liver will have a higherlikelihood of mortality (Fig. 3). The standardguidelines for liver replacement for any diseaseentity are used to determine if a patient willrequire a liver allograft together with theintestinal allograft (composite intestinal allo-graft). Likewise, relative and absolute contra-indications for intestinal transplantation followestablished recommendations for other organsand include the presence of untreated infection,malignancy, and a significant failure of other vitalorgan systems (principally the lungs and brain).Hepatic damage which is thought to be reversiblewill require transplantation only of the intestine.In our experience, true short gut (n563, 75%) wasthe most common cause of IF, followed bydysmotility/enterocyte failures (n519, 23%), andintestinal neoplasms (n52, 2%).

Intestinal allografts in their various forms

The canine operations performed by Lillehei (7)and Starzl (8) have set the template for allvariations of intestinal allografts which have beenperformed in most clinical series. The funda-mental strategy of multivisceral organ retrievalfocuses on isolating the organs that will beprocured for each individual recipient, and corecooling them with an infusion of a preservationsolution (the University of Wisconsin solution).Multivisceral on-block retrieval which includesthe stomach, duodenum, pancreas, liver and thesmall intestine is the parent operation whichbases its blood supply on the celiac and superior

Fig. 4. Modified cluster graft used toreplace resected viscera after upperabdominal exenteration. Notablewith this technique is the ability toretain variable amounts of intestine.(Reproduced with permission fromref. 55.)

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mesenteric arteries. This operation was appliedclinically for the first time in 1987, and fosteredseveral similar cases around the world (10).

Subsequent modifications in the procurementtechnique and allograft type by Starzl allowed fora limited transplantation of intestinal segmentsafter upper abdominal exenterations for malig-nancy (21) (Fig. 4). The initial success with thisoperation, however, was marred by the poorsurvival in this patient population due torecurrence of tumor (22). Grant from London,Ontario (12) and later Sindhi from Nebraska (23)allowed for a greater flexibility in graft type bylimiting the composite allograft to the liver andsmall bowel in its entirety. The elimination ofstomach, duodenum and pancreas seemed tofacilitate the peri-operative course, while allowingfor an increased survival of the patient and graft.The retrieval of other separate thoracic andabdominal organs (i.e. pancreas and kidneys)was facilitated by modifications introduced byAbu-Elmagd (24). In the early phase of ourclinical experience we included allograft colon,with the expectation that this would improvewater absorption and stool excretion, therebyfacilitating the TPN wean. This, however, did notoccur; more importantly, there was an increase in

peri-operative infectious complications. It wasclear that composite intestinal allografts shouldonly replace ‘failed’ parts of the gastrointestinaltract, avoiding unnecessary ‘multiorgan’ trans-plants with their inherent risk of increasedmorbidity and decreased survival (25).

Appropriate cadaveric intestinal donor cri-teria includes age less than 45 yrs (our experi-ence has included a range of 4 days to 34 yrs,with a median of 2 yr), hemodynamic stability(less than two vasopressors, limited cardiacarrest time to less than 30 min), and identicalABO blood type. Liver function tests shouldshow minimal ischemic damage to the liver, andserologic viral markers should be negative,except for cytomegalovirus (CMV) positivedonors who are only considered for CMVpositive candidates or for patients who areawaiting a concomitant liver allograft. Systemicand enteral antibiotics are given to the donorand focus on treating peri-operative bacterialtranslocation which may be associated withischemic damage of the intestinal allograft.Prophylaxis for GVHD with graft pretreatmentusing irradiation or a monoclonal anti-lympho-cyte antibody to deplete the lymphoid popula-tion has not been performed in our pediatricseries. In our experience, human leukocyteantigen (HLA) matching has been randomand uniformly poor, with no examples ofzero- A, -B or -DR mismatches. The T-celllymphocytotoxic crossmatch was positive afterdithiothreitol (DTT) treatment in 24 (29%)cases.

Isolated intestine

The small intestine, from the ligament of treitz tothe ileo-cecal valve, is procured and based on thesuperior mesenteric artery and vein; when thepancreas allograft is to be utilized in a separaterecipient these vessels are transected inferior anddistal to the pancreas (24) (Fig. 5). Vascularhomografts of the iliac artery and vein areprocured from the same donor to facilitateimplantation. This type of allograft is ideallysuited to patients with IF who do not havesignificant liver disease.

Liver and small intestine

This type of allograft utilizes a ‘duodenal-sparingcomposite liver intestine technique’ which pre-serves the head of the pancreas and thepancreatico-duodenal arteries (26). This is essen-tially an extension of the modified cluster graftpreviously utilized for upper abdominal exentera-

Fig. 5. In situ separation of the intestinal graft and dissectionof the superior mesenteric pedicle. Note preservation of boththe inferior pancreaticoduodenal artery (IPDA) and inferiorpancreaticoduodenal vein (IPDV) with the pancreatic graftby limiting the dissection of the superior mesenteric vesseis(SMV, SMA) below the level of ligated middle colic artery(MCA). (Reproduced with permission from ref. 56.)


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tion procedures (Fig. 6). This technique leavesthe entire pancreatico-duodenal complex and

small intestine with the liver allograft; it facil-itates both procurement and implantation, sinceit maintains the hepatic hilus intact, thusprecluding a biliary drainage procedure. Thearterial inflow is via the celiac and superiormesenteric arterial stems, with splanchnic venousflow of the intestinal allograft effectually creatinga donor superior mesenteric/portal venous axis;the entire ‘composite allograft’ venous outflow isthrough the hepatic veins. With this type ofallograft the pancreas is excluded as a benchprocedure; however, we have included it forpatients with established IDDM or evidence ofchronic pancreatitis with pancreatic exocrineinsufficiency. Besides allowing the utilization ofvery small donors (neonates), and permittinghepatic and intestinal reductions in cases wherethe allograft is too large for the recipient, it hasenjoyed easy applicability both here (27) and inEurope (28). This type of composite allograft isindicated in patients with IF who have significantliver disease.

Multivisceral graft

This type of allograft utilizes inflow through theceliac and superior mesenteric arteries and retainsthe liver, stomach, pancreas, duodenum andsmall intestine. The indications for this type ofgraft are limited to patients requiring extentera-tion of all the intra-abdominal organs (i.e.extensive motility disorders, diffuse splanchnicvenous thrombosis, and non-malignant tumors).It may also be modified by excluding the liverallograft and transplanting only the gastrointest-inal components of the allograft in patients who

Fig. 6. Composite liver-small bowel allograft with preservation of the duodenum in continuity with the graft jejunum andhepatic biliary system. The pancreas is transected to the right of the portal vein. The single Carrell patch containing the celiactrunk and superior mesenteric artery is anastomosed to a conduit of donor thoracic aorta. This technique allows reductions ofthe liver and/or intestinal components of the allograft. (Reproduced with permission from ref. 57.)

Fig. 7. Complete multivisceral graft; liver, stomach,duodenum, pancreas, and small bowel. (Reproduced withpermission from ref. 58.)

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do not require removal of their native liver(Fig. 7).

Implantation techniques

All intestinal allografts require the establishmentof an arterial inflow, venous outflow, andconnections to the native gastrointestinal tract.Transplantation of an isolated intestinal allograftdoes not require significant resections of nativeorgans or tissue, therefore it is a relativelystraightforward procedure. The larger compositeintestinal allografts however (liver/small boweland multivisceral) require extensive dissectionswith removal of the native liver, and sometimes acomplete abdominal exenteration. This is gen-erally performed in a setting of end stage TPNinduced cholestatic liver disease. The severecoagulopathy and portal hypertension is furtherconfounded by dense adhesions and massivesplenomegaly. It remains one of the mostchallenging procedures in surgery.

With isolated intestinal transplantation, anarterial homograft (donor iliac artery) isimplanted on to the native infra-renal aorta; avenous homograft (iliac vein) may be implantedon to the inferior vena cava (11 of our 23 cases),or portal vein (12 of our 23 cases). Venousdrainage into the native inferior vena cava is arelatively easier approach, and outcome resultshave not been affected by the type of venousdrainage utilized. The intestinal allograft is thenimplanted in its orthotopic position, anastomos-ing the superior mesenteric artery and vein to therespective homografts.

With liver/intestine and multivisceral trans-plantation, the recipients’ native failed organs areremoved. This is accomplished by stripping theliver off the inferior vena cava, preserving cavalcontinuity and maintaining the hepatic veins forthe venous drainage of the allograft. The supra-celiac or infra-renal aorta (according to prefer-ence) provide the source for arterial inflow via theimplantation of an arterial homograft (usually asegment of donor thoracic aorta). This facilitatesanastomosis to the aortic conduit of the allograftwhich will contain the celiac and superiormesenteric arteries (27). Intestinal continuity isre-established after successful graft reperfusion.Biliary drainage procedures are not necessarywith the duodenal sparing technique. Distalallograft ileostomies are fashioned using a‘loop’ or ‘chimney’ method. Both provide ade-quate access for surveillance endoscopies; how-ever, closure of the ileostomy is a relatively minor

procedure with the ‘chimney’ method, whereasthe ‘loop’ method will require a full laporotomy.

With liver/intestine transplantation, the nativesplanchnic venous flow is directed into therecipients’ inferior vena cava through a porto-caval shunt during the anhepatic phase.Previously, this was converted to a nativeportal vein to donor portal vein shunt afterimplantation of the graft to allow the hepato-trophic insulin-rich venous effluent from nativeintestine and pancreas first passage through theallograft liver (29). This, however, was found tobe unnecessary; presently the porto-caval shuntremains permanent.

Immunosuppression and clinical management

The introduction of tacrolimus in 1989 changedthe clinical applicability of intestinal transplanta-tion (15). The high initial success rate was notfollowed, however, by gradual graft acceptanceand the ability to taper immunosuppressivemedications as seen with the transplantation ofother organs. Repetitive episodes of rejectionwould result in late graft loss and mortality fromcomplications of rejection and the morbiditiesassociated with its treatment. Survival curves seenwith other organs such as the liver, kidney andheart, which generally plateau after the first post-transplant year were strikingly dissimilar. Withintestinal transplantation, where first year survi-val is impacted by rejection and peri-operativeevents, the subsequent complications of immu-nosuppression decreased survival up to the thirdyear post-transplant.

Transplantation of the intestine was tempora-rily suspended at our center between 1994 and1995 to allow an analysis of our initial experience.Six statistically significant risk factors for mor-tality were found: high tacrolimus levels, largeintravenous steroid usage, the administration ofmonoclonal anti-lymphoid globulin OKT3 (allreflective of the need to prevent and treatrejection), duration of the transplant operation(reflective of medical severity), inclusion ofallograft colon (variations in technique whichresulted in increased frequency of infection), andthe use of CMV positive donor organs in CMVnegative recipients (30). In order to improvesurvival, programatic changes were made after1995 which focused on: improved immunosup-pressive regimens which would decrease thefrequency and severity of rejection, therebydecreasing the morbidity of failure; the develop-ment of diagnostic tools for early diagnosis andintervention of opportunistic infections such as


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CMV and EBV; better selection of candidates,and simplification of both donor and recipientoperations (with exclusion of allograft colon)(31). This essentially divided our experience intotwo eras: 1990–94 and 1995–2001.

Immunosuppression for intestinal transplanta-tion is based on tacrolimus and corticosteroidinduction. This combination, however, hadlimitations which included breakthrough rejec-tion and toxicity. The addition of ‘third agents’ tothe maintenance regimen in order to preventrejection or to allow for decreases in Tacrolimusdosage due to the toxicity of this drug began after1995. This prompted the utilization of azathiopr-ine, cyclophosphamide, mycophenolate mofetil(MMF), daclizumab and most recently rapamy-

cin. The benefits of these regimens has beencontroversial, since there are no significantnumbers of patients enrolled in any one protocol;however, a review from the University of Miamisuggested improved outcomes (32). After 1994,mycophenolate mofetil (15–30 mg/kg/d) orazathioprine (1–2 mg/kg/d) were used selectivelyfor maintenance immunosuppression. BetweenMay 1995 and November 1997 we incorporatedcyclophosphamide (2–3 mg/kg/d for 4 weeks),however, it was discontinued due to significantmarrow toxicity and a high incidence of infec-tions. Daclizumab (Zenapax), a humanized IgG1monoclonal antibody directed at the alpha sub-unit of the human interleukin-2 receptor, wasintroduced as a third induction agent after May1998. This was given for a total of five intra-venous doses of 1–2 mg/kg, the first administeredprior to reperfusion of the allograft, with the re-maining four doses given at 2-week intervals (33).Since 1999, maintenance immunosuppression hasbeen with tacrolimus and prednisone used in con-junction with rapamycin (Rapamune1) at 1–2mg/m2/d for 2 weeks with dose adjustments tomaintain levels of 5–8 ng/dL. Tacrolimus levelsare maintained between 8 and 10 ng/dL using thisregimen.

Strategies to alter the lymphocyte populationof intestinal allografts were based on the fear ofGVHD and have been applied both in remoteand recent clinical series (10, 34). The nature ofsuch donor and recipient immunocyte migrationsbecame better appreciated as ‘genetic composites’with the critical experimental observations in ratintestine alone and multivisceral transplantperformed by Murase et al. (35). This wasconfirmed clinically by Iwaki et al. in humanrecipients of intestine alone and multivisceraltransplants (36). Since such leukocyte replace-ment had been observed after clinical livertransplantation, it was believed that this (micro-

Fig. 9. Photomicrograph of chronic rejection; notable is thesignificant blunting of surface epithelium and vasculopathy.

Table 2. Clinical features of children who received intestinal transplants duringthe periods 1990–94 and 1995–2001

1990–94 1995–2001 Total

Total no. of patients 34 50 84Prior abdominal operations 261 364Total no. of allografts 37 52 89

Intestine 8 16 24Liver/intestine 23 31 54Multivisceral 6 5 11

Positive cross-match 12 12 24Bone marrow augmentation – 16Induction therapy

No 34 29Yes 0 23

Splenectomy 19 18OKT3 17 18

Fig. 8. Endoscopic picture of acute rejection; notepseudomembranes over areas of mucosal exfoliation,interspersed between islands of intact and regeneratingmucosa.

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chimerism) was likely occurring with all solidorgan transplantation. Subsequent intestinaltransplantation research has focused on theparadigm that two cell populations (donor andrecipient) engage in mutually canceling immunereactions, with the eventual development ofvarying degrees of non-reactivity (16). To testthis hypothesis, bone marrow augmentation wasperformed by recovering bone marrow cells fromthe thoracolumbar vertebrae of the intestinaldonors and infusing them intravenously (a singleinfusion of 3–53108 donor cells/kg body weight)into 16 children within the first 12 h afterreperfusion (37–39). Bone marrow cells werenot available for 35 contemporaneous recipients,who were considered controls. Intravenous pros-taglandin E1 is also infused routinely during thefirst post-operative week.

Rejection therapy has included bolus steroidsas pulse and or tapering therapy, with OKT3 usedin cases of steroid resistant rejection. Recently,the use of thymoglobulin, a rabbit-derived anti-lymphocyte globulin (1–2 mg/kg/day) has beenevaluated in the treatment of five intestinalallograft recipients with steroid resistant rejec-tion. Four of the five of our patients responded toan average of 12 doses; one patient developedPTLD.

There is presently no clinically applicableserologic marker for the diagnosis of rejectionof the intestinal allograft. Endoscopic surveil-lance and biopsy through the allograft ileostomyprovides the only means of making this diagnosis.The introduction of zoom endoscopy by Katoet al. from Miami has enhanced endoscopicassessments of the intestinal allograft; however,

histopathology remains the gold standard (40).The clinical signs and symptoms of intestinalpathology may be significant or entirely absent.The criteria for histologic diagnosis of acuterejection relies on the presence of crypt celldestruction (apoptosis) in the setting of mixedlymphocytic infiltrate, with varying degrees ofseverity (41, 42). Varying degrees of destructionmay be present, producing endoscopic pictures ofswelling, erythema, ulcers, or diffuse mucosalexfoliation (Fig. 8). The diagnosis of chronicrejection (CR) is a recent observation afterintestinal transplantation. Clinically, CR presentswith chronic symptoms of diarrhea and bleeding;strictures and dilatations are seen radiographi-cally, with evidence of arteriopathy on angio-graphy. It appears to evolve from immunologicdamage to the intestinal epithelium and indirectdamage secondary to obliterative arteriopathy.Mucosal biopsies are characterized by loss of villiand crypts, a predominant plasmacytic infiltrate,and ulcerations (Fig. 9). These events may beassociated with acute rejection.

The clinical outcome for most solid organs haslargely been determined by the ability to preventand control rejection, which occurs at a rate ofbetween 70% to 95% with intestinal transplanta-tion. Improvements in the rate of rejection andclinical outcomes have been impacted by centerexperience, use of triple drug immunosuppres-sion, and the early diagnosis of opportunisticinfections (31, 34). Rejection of the isolatedintestinal allograft is significantly higher thanwith intestinal allografts that form part of acomposite graft (liver/intestine and multivisceralgraft), suggesting that the liver allograft isprotective of the intestinal allograft. This hasresulted in a higher graft loss due to rejection withthe isolated intestinal vs. the composite intestinalgrafts. Likewise, the need for OKT3 and theincidence of vascular and chronic rejection isalso higher with isolated intestinal allografts.Nonetheless, isolated intestinal transplantationcarries with it a significantly lower incidence ofperi-operative surgical and clinical complicationsthan recipients of the larger composite grafts.Consequently, the overall survival of isolatedintestinal transplantation is superior, therebyjustifying the transplantation of patients withIF before they develop liver failure (42).

The inability to prevent or successfully treatrejection of an intestinal allograft may then resultin evidence of graft dysfunction, drug toxicitiesand opportunistic infections. Graft dysfunctiondue to rejection is a consequence of a breakdownin the normal barrier function and may manifest

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as bacterial translocation, sepsis, graft necrosisand abscess, or intestinal obstruction. Bleedingmay occur due to mucosal exfoliation. Allograftenterectomy and return to TPN is only possiblewith recipients of isolated intestinal grafts, andthe survival of such patients will depend on thestability of the factors which warranted the initialintestinal transplant. Consequently, after graftenterectomy many patients will die of sepsis,thrombotic events or liver failure. Few retrans-plantations have been performed; some patientshave later required a liver/intestinal allograft afterfailing a primary isolated intestinal transplant.Recipients of failed composite grafts will requireimmediate retransplantation. Success with intest-inal retransplantation has been poor, and as aconsequence, consideration for this should behighly selective (43).

Infections as a consequence of the higher levelsof immunosuppressive drug therapy and need totreat rejection in our pediatric intestinal trans-plant series have been principally due to cytome-galovirus (CMV) (22%), and Epstein–Barr Virus(EBV) (31%) (44). With present techniques forthe early detection of CMV (pp65 anti-genemia)the management of this infection has been greatlyimproved (45). Treatment regimens for CMVhave included ganciclovir (DHPG) and cytogam;withdrawal or reduction of immunosuppressionmust be limited due to breakthrough intestinalallograft rejection. The resolution of CMVdisease has been accomplished in over 95% ofcases; it is no longer a significant cause for patientor graft loss.

EBV was recognized as a major cause ofmorbidity and mortality following pediatricintestinal transplantation during the early experi-ence with this procedure, with an incidence of

PTLD exceeding 25% (46). PTLD in intestinaltransplant recipients is complex, principallybecause a significant decrease or withdrawal ofimmunosuppression has resulted in severe break-through intestinal allograft rejection, with con-sequent high mortality (Fig. 10). EBV may causea wide range of diseases ranging from a non–specific viral syndrome to PTLD. Significant riskfactors for development of the disease include theuse of OKT3 and splenectomy (Fig. 11).

In 1994, we began a program of serialmonitoring of the EBV viral load in theperipheral blood (quantitative competitive poly-merase chain reaction assay, QC-PCR) coupledwith a pre-emptive therapy (PT) strategy in aneffort to protect against this complication (47).Pre-emptive therapy consisting of i.v. ganciclovir(10 mg/kg/d), CMV-IVIG (300 mg/kg every3 weeks), and where possible, reduction in


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80

70

100

90

2 6 10

Primary Gx survival

8

(b)

Fig. 12. Overall patient (A) and graft (B) survival. Notable isprogressive decrease up to 3 yr post-transplant, wheresurvival seems to plateau.

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immunosuppression was initiated for EBV viralloads i 40 and i 200 genome copies/105 PBL,for patients whose pretransplant serostatusagainst EBV was negative and positive, respec-tively. Incidence and outcome of EBV/PTLD inthese monitored patients was compared to acohort of children undergoing intestine trans-plantation at our institution prior to the avail-ability of viral load monitoring.

Fifty-one children (including 34 EBV sero-positive, 16 EBV seronegative and one EBVunknown) underwent intestine transplantationbetween 7/94 and 1/2001. Twenty-three out of 51patients developed elevated viral loads promptingpre-emptive therapy (18/34 seropositive, 4/14seronegative, p5N.S.). The median time tofirst initiation of pre-emptive therapy postintestinal transplantation was 69 days (69 daysin seropositive, 93 days in seronegative). PTLDdeveloped in 7 of the 23 children despite pre-emptive therapy. PTLD also developed in twochildren who complied with the monitoring butpresented with PTLD at the time of their firstelevated viral load. Three additional patientsdeveloped PTLD who were not compliant withour monitoring or pre-emptive therapy protocol.Thus the frequency of EBV/PTLD in the era ofEBV monitoring was 12/51. Six of 12 of thesepatients with a history of PTLD are currentlyalive without loss of their graft. In contrast,PTLD developed in 15/34 children undergoingintestinal transplantation in the premonitoringera and was associated with death (n510) or graftloss (n51) in 11/15 children with this complica-tion. The odds ratio of developing PTLD in themonitoring compared to non-monitoring era was0.39 (95% C.I.: 0.14–1.10) and of dying or losing agraft after PTLD was 0.36 (95% C.I.: 0.05–2.35).The use of monitoring and pre-emptive therapyappears to have decreased the incidence andimproved the outcome of this complication inthese patients. Unlike recipients of other solidorgan transplant procedures, EBV seropositivityprior to intestinal transplantation does not resultin a diminished risk of developing PTLD afterintestinal transplantation in children.

Center experience of 11 yrs (a tale of two eras)

Intestinal transplantation under tacrolimus/pre-dnisone immunosuppression was initiated atour institution on 24 July 1990. Our experienceis divided into two eras (1990–94 and1995–2001) as described in the previous section(Table 2). Principle reforms included triple drugtherapy, the use of the duodenal preserving

liver small bowel graft and exclusion of colon,and pre-emptive therapy for CMV (using PP65anti-genemias) and EBV (using QC-PCR).


0 4

Cum

ulat

ive

surv

ival

(%

)

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0

10

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30

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50

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31 5 7

(a)


0 4

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30

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(b)

1990–19941995–2001

1990–19941995–2001

Fig. 13. Comparative patient (A) and primary graft (B)survival between two eras: 1990–94 vs. 1995–2001.

Table 3. Types of intestinal grafts

Children (n589)

IntestinePrimary 23Retransplant 1

Total 24 (27%)Liver/Intestine

Primary 51Retransplant 3

Total 54 (61%)Multivisceral

Primary 10*Retransplantation 1

Total 11 (12%)

*Modified multivisceral (without liver) (n52).


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Eighty-four children with ages ranging from6 months to 18 yr (mean age 4.964.8 yr)received 89 allografts. There were 84 primarytransplantations, and five retransplantations ofthe three different kinds of allografts werecarried out over the 11-year period (Table 3),73% of which consisted of liver and intestine ormultiple abdominal viscera (isolated intestine24, liver/intestine 54, and multivisceral 11), 45(54%) were male. Donors were ABO identical inall but one emergent case (ABO compatible).The causes of IF were short gut (n563) in 75%,dysmotlity/enterocyte failure (n519) in 23%,and tumor (n52) in 2%. Short gut was due tovolvulus (n522), gastroschisis (n519), intestinalatresia (n510), necrotizing enterocolitis (n510)and trauma (n52). Of these 84 patients, threechildren had previously received an isolatedhepatic allograft for a diagnosis of biliaryatresia, familial cholestasis, and TPN inducedliver disease. They required intestinal transplan-tation 4–10 years later for a diagnosis of mid-gut volvulus (n52) and intestinal pseudo-obstruction (n51). The five retransplantationswere performed with isolated intestine (n51),liver/intestine (n53), and multiple abdominalviscera (n51). Three retransplants were per-formed in the first era, and two in the secondera. The intestine only retransplant was per-formed 11 months after graft enterectomy forPTLD and chronic rejection. One of the liver/intestinal allogafts was used to rescue a primaryintestinal recipient, and the other two were usedto replace acutely failing primary liver/intestinalallografts. The one multivisceral transplant wasperformed in a recipient failing a primary liver/intestine transplant. Immunosuppression for allpatients was based on tacrolimus and corticos-teroids. Third agents were incorporated princi-pally after 1994 according to the schemadelineated in the previous section, and haveincluded azathioprine (n516), mycophenolatemofetil (n52), and rapamycin (n518).Induction therapy with Daclizumab was usedonly after 1994 and included 23 transplants.

Forty-five patients (54%) are currently alive1–126 months post-transplantation (mean of53 months). The Kaplan–Meier actuarial survi-val for this pediatric population at 1, 3 and5 years post-transplant was 74%, 59% and 56%for patients and 67%, 53% and 47% for grafts,respectively (Fig. 12). The majority of the deathsoccurred within the first 3 post-operative years,the causes of which included infection, technical/graft failure, and rejection (Table 4). The mor-tality in the first era was higher (22/34, 64%) thanin the second (17/50, 34%).

Patient as well as graft survival improvedafter 1994 (Fig. 13) the early cohort of 34recipients showing a 1, 3 and 5-yr survival of66%, 50% and 47%, respectively, vs. the 50recipients after 1994 of 77%, 68% and 64%,respectively. Forty-five (54%) of the 84 recipi-ents are currently alive, of whom 39 (87%) arecurrently off TPN; 15 recipients (5 isolatedintestine, 9 liver/intestine, and 1 multivisceral)have survived beyond 5 yr. Recipients ofisolated intestinal allografts had the bestcontinued survival beyond 5 yr.

There were 345 episodes of rejection in these89 grafts (3.9 episodes/patient), with no evi-dence of rejection in 16 grafts (18%). Severerejection requiring treatment with OKT3(n535) and/or thymoglobulin (n55) occurredin 43% of the grafts. The incidence of rejectionduring the first 30 postoperative days wassignificantly higher during the 1990–94 (85%)than those of the 1995–2001 (67%). The use ofDaclizumab appeared to be the principal factorin reducing the incidence of early post-trans-plant rejection during the second era.Refractory rejection was the primary cause offailure in 13 out of the 89 grafts: 9 intestineonly, 3 liver/intestine, and 1 multivisceral for anincidence of 37%, 6% and 9%, respectively.

Forty-two clinical variables were analyzed ineach of the 85 children, aged 6 months to17.4 yr, receiving primary isolated intestinetransplantation (n525), liver/small intestine(n551), and multivisceral (n59), for correlationwith incidence, number, severity and time toacute rejection episodes, and for associationwith death and graft loss. Clinical variablesincluded donor and recipient demographics,antigenic characteristics, preservation timeand immunosuppressive therapy. All childrenreceived tacrolimus and steroids. A third agentwas used for induction in 46 children.

Acute rejection was encountered in 74/85 child-ren, with 59 children experiencing more than twoepisodes. Acute rejection episodes occurred earlier

Table 4. Cause of death after intestinal transplantation

Infection Rejection PTLD Technical Others Total

Isolated intestine* 5 3 0 0 4 12Liver/intestine 5 3 6 4 3 21Multivisceral 3 1 2 0 0 6Total 13 7 8 4 7 39

PTLD 5 Post-transplant lymphoproliferative disease.*Two had undergone graft enterectomy.

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after liver/intestine transplantation comparedwith isolated intestine transplantation (p50.043),among recipients with blood group A comparedwith blood group AB (p50.05), and in those withHLADR mismatch compared with HLADRmatch (p50.0214). Rejection-free survival wasassociated with the use of a third agent, zenapax(p50.018). Although acute rejection was not seenin five children receiving sirolimus as a third agent,statistical significance was not seen, most likely dueto the small numbers of treated patients. Similarly,enhanced graft survival was associated with the useof zenapax (p50.001), and thymoglobulin treat-ment for acute rejection (p50.0376). A significanttrend towards decreased patient survival was seenfor liver/intestine transplantation (p50.009),HLA-A mismatch.HLA-A match (p50.044)and modified multivisceral transplantation(p50.046), and for increasing cold ischemia time(p50.01).

Among factors that can be manipulatedtherapeutically, immunosuppressive regimenscontaining three agents may improve rejection-free survival after intestine transplantation.Furthermore, the aggressive management ofrejection episodes with newer treatments suchas thymoglobulin, and minimizing preservationinjury may also prolong survival after pediatricsmall bowel transplantation.

Chronic rejection was diagnosed in 5 (21%)isolated intestine allografts, and 1 (2%) liver/intestine allografts. The diagnosis was made in allcases by histopathologic examination of enter-ectomy specimens. Four of these children pre-sented with distal ileal allograft obstruction andwere treated with segmental ileal resection. Twoof these patients recovered, although onerequired a repeat resection. Two childrenrequired graft enterectomy, one as primarytherapy and one following an attempt at partialresection. Changes consistent with obliterativearteriopathy were confirmed in all cases.

The reciprocal phenomena to rejection, knownas graft-vs.-host disease (GVHD), occurs whenimmunocompetent donor lymphoid cells damagethe recipient tissues after allogeneic transplanta-tion. This complication had been greatly fearedafter clinical intestinal transplantation becausethe large inoculum of lymphoid cells contained ina small bowel allograft was predicted to increasethe likelihood of this process. GVHD targets theepithelial cells of the skin, native intestine andliver. In our experience, GVHD was histologi-cally documented in seven children (8%), andonly two patients had received bone marrow. Theonset varied from 6 days to 8 yr following

transplant. Donor/recipient sex mismatch waspresent in 6/7 cases. The incidence of GVHD wasnot affected by donor bone marrow infusion,splenectomy, or incidence of positive or negativecytotoxic cross-match.

One previously reported child with an immu-nodeficiency disorder characterized by low IgAand IgG levels died from GVHD after anintestine/liver transplant (48). GVHD resolvedsatisfactorily in the other six patients who weretreated with augmented immunosuppression inthe form of steroid therapy and optimization oftacrolimus therapy.

Life after intestinal transplantation: Conclusion orcontinuum

Life after intestinal transplantation is challengingto say the least. As survival rates increase forintestinal transplant recipients and an extendedsurvival of greater than 5 yr is observed, qualityof life issues are becoming a benchmark forsuccess. For approximately 6–12 months post-transplantation, the care routines of pediatricpatients may include 7–15 daily medications, tubefeedings, i.v. fluids, and the maintenance of agastrostomy tube or jejunostomy tube, intestinalstoma and venous access. These routines gen-erally decrease over time as a result of ostomyclosure, increased oral intake, and removal ofappliances. However, a mean of seven daily ortwice daily medications is still required at greaterthan 3 yr post-transplantation, and 17% ofpatients continue to require enteral feeding dueto oral aversion. Over 80% of patients who areschool age are attending school full-time at 3 yrpost-transplantation, or have returned to schoolat the appropriate level (49, 50).

In a study of parents whose children hadreceived liver and/or intestine transplants, amajority of parents reported elevated psycholo-gical symptoms, with fathers showing greaterdistress than mothers. Although parenting stresswas not elevated when compared to a normativesample, having a younger child going throughtransplantation was associated with higher stress.Parents reported better physical function, butlower vitality than the normative population (49).

Psychiatric and psychosocial problems affect-ing quality of life following intestine transplanta-tion are a function of severity of disease, durationof preoperative TPN, length of pretransplantwaiting period, and prolonged post-operativecourse; thus vary inversely with available socialsupport (50). In the early post-operative period, ahigh incidence of affective disorders such as


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depressions and anxiety related to post-operativeadjustment has been reported (51).

Assessing quality of life in intestine transplantrecipients is challenging due to significant patientvariability with respect to underlying disease, thepost-operative course, long-term complications,and psychosocial factors. It is imperative, how-ever, that quality of life be evaluated as morepatients are offered this therapy to help themmake the best decisions for their care, and toguide the transplant team in implementingmedical management and therapy (52, 53).

Historical summary

The development in technique and immunosup-pressive management of the last 12 yr havemade intestinal transplantation an effectivetreatment for children with intestinal failure.The information provided in this review sup-port such a conclusion, but was more clearlyvalidated by the March 2001 Medicare Reportwhich provided a national coverage decision ofthe Social Security Act for intestinal transplan-tation.

As of May 2001, there were 55 centers world-wide which have performed 696 intestinaltransplants in 656 patients. (IntestinalTransplant Registry, http://www.lhsc.on.ca/itr)the majority of recipients have been children,and there has been a greater need for liverreplacement in conjunction with the allograftintestine because of a higher incidence of TPN-induced cholestatic liver disease in children.Though overall long-term survival is approxi-mately 50%, similar advances in surgical,clinical and immunosuppressive managementsince 1995 have improved patient survival tomore than 70% in most experienced programs.Over 80% of survivors are enjoying nutrition-supporting intestinal function. The major causesof graft loss and patient demise continues to berejection and infection. Tacrolimus remainsthe mainstay of immunosuppressive therapy.Further experience other induction protocolsutilizing rapamycin and daclizumab, as wellgraft pretreatment protocols may furtherenhance results in the future.

Acknowledgements

This work was supported by research grants from the Veterans

Administration Project Grant no. DK29961 – National Institutes of

Health, Bethesda, Maryland, USA.

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Pediatric intestinal transplantation: Historical notes, principles and controversies

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