Advances in Small Bowel Transplantation Alp Gürkan

Internal Medicine Review Small bowel transplantation March 2016

Correspondence: ABSTRACT Alp Gürkan, MD, FACS, Small bowel transplantation (SBT) is a life saver procedure in Professor in Surgery, patients with intestinal failure. The biggest obstacle to Head of tTransplantation Dept. intestinal transplantation is graft rejection. It is the main factor Çamlıca Medicana Hospital. in morbidity and mortality. Rejection has a negative impact on Organ Transplantation Dept, survival of the graft. The acute rejection occurs in 50-75%, and Alemdag Caddesi No 113 the chronic rejection occurs in 15% of the patients. Uskudar, İstanbul, Turkey, Immune monitoring is crucial after SBT. Unlike other types of Phone: + 90-532-266 79 38 transplantation, the intestine lacks a reliable and minimally Fax: +90-216-521 30 33 invasive marker to predict rejection. The diagnosis of acute E mail: [email protected] rejection is performed by clinical, endoscopic and pathologic [email protected] anatomy. Protocol biopsies and histological analysis remain the gold standard for allograft monitoring, but neither is free of complications, especially in smaller grafts. Up to 30% of biopsies are nondiagnostic and multiple biopsies may be required to exclude rejection. So, ancillary assays are increasingly used in SBT such as measurements of citrulline and calprotectine in the blood, cytofluorographic analysis of peripheral immune cell population, cytokine profiling and the quantitation of distinct gene set changes. Developments in the understanding of genes provide promise that limited gene sets, taken from blood or from intestinal biopsies, will enhance pathological diagnosis. Bone marrow mesenchymal stem cell transplantation with SBT and tissue engineering are promising procedures.

Keywords: sSmall bowel transplantation; intestinal

transplantation; stem cell transplantation; intestine

No sponsorship is provided for this paper.

The author did not have any kind of conflict-of-interest.

Internal Medicine Review Small bowel transplantation March 2016

INTRODUCTION Although there are variations of The small bowel transplantation (SBT) has terminology, the current classification developed less, when compared to other includes four groups according to the solid organ transplantations. Currently, it is inclusion of the liver and/or the stomach in the only chance of cure for patients with the graft: isolated, liver-intestinal, intestinal failure who develop multivisceral and modified multivisceral complications related to the use of transplantation.3 Although combined liver parenteral nutrition. The number of SBT is and intestine was the most common type relatively small compared to all other of small bowel graft in the past, the types of solid organ transplantations. frequency has declined from 68% in 2007 Although declining in volume in the to 39% in 2011. Isolated small bowel United States since 2007, probably due to transplantation (including stomach, bowel rehabilitation programs and recent pancreas or colon) has been increasing in developments in surgical techniques such frequency.4 There is a need for intense as tapering enteroplasties, the number of immune suppression because of the large small bowel transplantation increased immune response to the graft. Thus, substantially in the last 5 years in Europe, opportunistic infections and neoplastic China and Japan.1 It is estimated that 2-3 diseases are more prevalent compared to people per million inhabitants per year had other solid organ transplants. Due to the intestinal failure of whom 15% are large amount of tissue transplanted, graft candidates for SBT for irreversible versus host disease (GVHD) is also more intestinal failure and complications of prevalent in comparison to other solid parenteral nutrition.2 The mortality in this organ transplantations. Finally, it is the group is high, reaching 40% at five years most expensive transplant procedure.

in patients having less than 50 cm of Currently, the failures of parenteral healthy small bowel left due to infections nutritional therapy are candidates for SBT. and/or thrombosis of vessels and having Complications of parenteral nutrition liver disease. usually accepted as indications are: SBTs are complex procedures in patients thrombosis of two of the six major venous with compromised clinical conditions. It accesses; liver disease; episodes of comprises of a number of surgical catheter-related infections (two or more procedures of which the principal is the per year, fungemia, shock or respiratory transplantation of the small intestine. failure); alterations of growth and

Internal Medicine Review Small bowel transplantation March 2016 development in children and refractory (Figure 1) is indicated in the presence of electrolyte changes. Patients dependent on irreversible intestinal failure in the absence parenteral nutrition without complications of severe hepatic dysfunction. The are not candidates for intestinal determination of liver disease severity and transplantation, nowadays. reversibility is held more securely by liver biopsy. The presence of bridging fibrosis Surgical techniques or cirrhosis indicates the necessity of The SBT can involve some others replacement of the liver. A recent study abdominal organs to be transplanted with showed an association between the levels the small intestine. The severity of the of bilirubin, platelet count and albumin liver disease determines the organs to be level in the presence of liver failure in transplanted, so that patients with mild children in parenteral nutrition.5 liver disease (no evidence of portal hypertension, mild hepatic fibrosis on liver The arterial anastomosis is established biopsy) can be offered an isolated through the superior mesenteric artery intestinal, or a modified multi-visceral graft to the aorta. The venous drainage is graft, including stomach if dysmotility of made through the superior mesenteric vein the foregut is a prominent clinical to the inferior vena cava (Figure 2) or the problem. The preferred technique is the mesenteric portal system. The venous composite graft where the liver and drainage into the portal system should intestine with bile ducts, duodenum, and always be preferred due to its physiologic head of a pancreas can be implanted en and possible immunologic advantages but bloc with minimal disruption to the depends on the technical feasibility of vascular and other structures connecting accessing the recipient portomesenteric the organs; or the organs can be retrieved axis. In patients with modest portal from the donor, separated, and implanted hypertension presented with mild splenic individually, which is known as non- enlargement, for whom the decision has composite combined liver and small bowel been made to perform isolated small bowel transplantation. The selection of organs to transplantation in the absence of low be included will depend on the underlying platelet counts, gastroesophageal varices, disease, quality of other abdominal organs, and intrahepatic cholestasis, the venous presence and severity of liver disease and outflow should be drained into the the number of previous abdominal recipient IVC. Other studies showed no surgeries. The isolated small bowel graft difference in survival, however, the “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 3

Internal Medicine Review Small bowel transplantation March 2016 cumulative episodes of infection rate by pancreatoduodenal arc graft. This avoids bacteria of the gastrointestinal tract was the dissection of hilar structures, which higher in patients with systemic drainage, can be difficult in small children. suggesting a protective role of the liver.6 Alternatively, liver and intestine can be Anastomosing to portal vein is more transplanted separately which has the technically demanding but does offer advantage that if the intestinal graft should restoration of physiological drainage of the develop severe rejection, it could gut via the portal system. In practice, potentially be removed without requiring anastomosing to mesenteric superior vein retransplantation of the liver. But, the is technically easier and is seldom disadvantage of this technique is that it associated with major problems in terms of requires multiple vascular anastomosis and outcome. biliary reconstruction with the attended

In all types of SBT an ileostomy is risk for complications. performed for endoscopic surveillance, Controversies exist regarding the inclusion facilitating the diagnosis of rejection and of the colon and spleen grafts. Patients perfusion disorders. who received an intestinal graft without

Combined liver and small bowel ileocecal valve usually do not have well- transplantation offers a treatment option in formed stools and are more likely to cases where there is irreversible liver become dehydrated. It was thought that damage and has been more commonly inclusion of the colon in small intestine applied in pediatric cases, where PN grafts increases the risk of graft failure or related liver disease has been more of a death rate, so it has previously been problem than in the adult population. This avoided. But, recent studies showed that group of patients competes for scarce liver inclusion of the colon did not increase grafts. U.S. data show that 74% of the morbidity or mortality and bloodstream patient candidates for intestinal infections, but only brought benefits 8 transplantation require an associated liver.7 especially in pediatric patients.

Enhancement of allocation models and Preservation of the native liver, spleen and early referral to SBT can be a solution to pancreaticoduodenal complex when this problem. The grafts can be deployed possible has had a great influence. These separately, or in a more convenient way, en different modifications are applied for bloc. To maintain the liver and intestine en patients who are in need of multivisceral bloc, it is necessary to include the transplant with preserved liver functions, “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 4

Internal Medicine Review Small bowel transplantation March 2016 particularly those with Gardner and suited to be performed with 1 or 2-hour pseudo-obstruction syndromes. Sparing intervals.

the native spleen also has potential Loss of the abdominal domain in small advantage of reduced risk of post- bowel transplant recipients due to transplant lymphoproliferative disorder. extensive adhesions, secondary to multiple After showing the beneficial effect of prior surgeries, shortage of appropriate spleen transplantation in promoting recipient size matched donors, abdominal 9 tolerance in animal experiments, a recent wall scarring due to fistulas, ostomies research demonstrated that adding the repeated laparotomies and post perfusion spleen to the multivisceral transplantation graft edema make the primary abdominal graft yielded better outcomes in terms of wall closure difficult. A primary tension low acute rejection without altering the free closure of the abdominal wall is 10 incidence of GVHD. Inclusion of the achievable in 50-85% of recipients. Aside donor spleen with the multivisceral graft from reduced-size grafts to facilitate the was also introduced with the notion of primary closure, various strategies have reducing infection and enhancing mixed been introduced to reconstruct and enlarge chimerism. the abdominal wall. Some of the strategies

Other notable contributions include en that have been employed are usage of bloc retrieval of the distal esophagus with tissue expanders, staged abdominal closure the multivisceral graft which facilitates to with mesh, bioengineered skin equivalents, harvest foregut organs. acellular dermal matrix, vascularized or

Although it is not used widely, nonvascularized rectus muscle fascia microendoscopy helps to visualize the grafts, skin grafts and finally vascularized transplant mucosa and to monitor the abdominal wall transplantation from same 12,13 blood flow during the surgery. Upile et donor. Abdominal wall transplantation al.11 argue that the method is of value allows primary skin and abdominal wall intraoperatively as well as in the closure without causing abdominal postoperative period, and that monitoring compartment syndrome. But, it has some can be performed from the serosal or the disadvantages like the need for complex mucosal surface of the transplant. Thus, vascular anastomosis, longer operative this method helps to assess the viability of time and higher morbidity rate. The use of the graft. But, as with endoscopy, the avascular rectus allofascia is also reported 14 procedure is very demanding and not with good results. “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 5

Internal Medicine Review Small bowel transplantation March 2016

Donor preparation Living donor small bowel transplantation Ideal donors are preferably younger and is a relatively new type of transplantation with little or no vasoactive drugs. Patients which is suitable especially for children with short bowel syndrome have the with intestinal failure who develop acutely abdominal cavity retracted, and need the decompensated liver failure. It can be usage of smaller donors (30 to 40%). With performed successfully simultaneously or the development of effective drugs for sequentially to reduce the morbidity and prophylaxis and treatment of mortality while waiting on the list. Small cytomegalovirus seropositive donors are bowel grafts consisted of 150 cm of an accepted, avoiding only for receivers with ileum segment with or without left lateral negative serology. Decontamination of the liver graft depending on the liver function gastrointestinal tract and use of antibodies of the patients. A largest case series article in donor lymphocytes showed no benefits reports that none of the donors changed related to infection, rejection episodes or their life style, work habits, or psychologic incidences of GVHD. These donors are condition after donation.16 also suitable for harvesting liver and Organ preservation pancreas grafts. The grafts sharing the The University of Wisconsin (UW) same bloodstream bring challenges to the solution has been considered the gold simultaneous harvesting of these grafts, standard for the preservation of all organs but is possible to perform the procedure of the digestive system. However, there are without compromising the graft.

reports about the usage of other solutions, Intestinal mucosa is sensitive to ischemic like Celsior, and HTK which gives similar injury. When the intestinal graft is results as the UW solution in ischemic harvested from non-heart beating donors periods up to 8 h in SBT. Although there is (NHBDs), the infectious-related mortality no significant difference in terms of graft was higher and the absorptive function survival, initial function, endoscopic lower. Histological examination confirmed appearance or transplant pancreatitis a higher grade of ischemic injury in the between HTK and UW as preservation NHBD grafts that correlated with the solutions in small bowel grafts, HTK has clinical data. An experimental study the advantage of better flushing the suggested that non-heart-beating donation microvasculature due to its low viscosity.17 may not be suitable for small bowel 15 transplantation. “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 6

Internal Medicine Review Small bowel transplantation March 2016

Postoperative management and highly chimeric.17 Thus, the presence of complications recipient lymphocytes within intestinal Surgical complications (bleeding, fistula, submucosa may not necessarily indicate a dehiscence and wound infection) may process of rejection. This bidirectional cause episodes of rejection and exchange of immune cells is responsible opportunistic infections, postoperatively. for GVHD with 7-13% incidence rate.18,19 The biggest obstacle to intestinal The incidence, risk factors and impact on transplantation is graft rejection. It is the survival of GVHD were analyzed in a main factor in morbidity and mortality. retrospective study.18 Risk factors for Rejection has a negative impact on GVHD were young age, multi-organ graft survival of the graft. The acute cellular recipients and splenectomized cases. The rejection occurs in 50-75% of patients, potential role of donor T cells in the most commonly in the first 90 days. pathophysiology of GVHD has been Chronic rejection occurs in 15% of analyzed.18 The study showed that levels patients.18 The consequences of severe of donor derived T cells chimerism rejection are considerably higher than correlates with clinical course of GVHD. other solid organs with 50% mortality rate.

Out of 11 patients, 64% showed clinical Immunological complications features of GVHD with all of them having SBT represents a major immunological detectible donor T cell chimerism. The challenge compared with other solid study reported that all the patients organs as more than 80% of the immune responded to increase in immune cells inhabit the small intestine. Previous suppressive therapy, and three of them reports have suggested that the small died due to sepsis and multiorgan failure. intestinal allograft (particularly the ileum) Another immunological complication is is the most susceptible organ to acute inflammatory bowel disease-like disease rejection (AR) in frequency and severity (IBD) after transplantation. The incidence when compared with other allografts and it of IBD in the patients with solid organ has been recognized as the “Achilles heel” transplantation is 10 times more than the and critical organ of multivisceral expected incidence of IBD in the general transplantation. Besides, after the population.20 Posttransplant IBD is transplantation, the small intestine is correlated with cytomegalovirus infection, repopulated with recipients’ enterocytes Epstein-Barr virus, posttransplant lympho- within 10 weeks, which makes the graft proliferative disorder and use of “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 7

Internal Medicine Review Small bowel transplantation March 2016 tacrolimus.21 Another possible mechanism layer after 168 h reperfusion during the can be the donor lymphocytes having the manifestation of AR.24

genetic information for an abnormal Rejection inflammatory response. The intestinal The diagnosis of AR is performed by inflammation coming from failure of clinical, endoscopic and pathologic physiological control by regulatory donor- anatomy. The gold standard for the derived T cells may manifest as an Arthus- diagnosis of acute cellular rejection is 22 like reaction in the colonic mucosa. In a histology. The routine ileostomy facilitates study, the usage of anti-TNFα showed endoscopic assessment and biopsies. The dramatic clinical and histological endoscopic surveillance is held two to 23 improvement in two children. Anti-TNFα three times per week in the first three therapy also has some benefits in treating months, being held once a month from steroid and thymoglobulin resistant AR then and according to the situation.27 A episodes. number of endoscopic findings may be

In the process of AR, gene expression of associated with AR: mucosal erythema, TNFα is upregulated early after congestion, shortening and flattening of transplantation with a further increase as the villi, friability and ulcerations. previously described,25 which is known to Endoscopy alone has a sensitivity of only be associated with immune regulatory 52% but a specificity of 93%.27 On processes, activation and induction of suspicion of rejection several biopsies apoptosis and T cell proliferation.25 In should be performed because the lesion several case reports, infliximab has been can spare a few segments.

shown to be a therapeutic option for AR, One important consequence of local innate especially in patients with refractory immune activation is increased activity of 26 rejection. antigen presenting cells, which, in turn,

can increase sensitization to donor TNFα mRNA-expression is slightly antigens. Use of the lymphocyte-depleting elevated after isogenic and allogenic agents for induction, and long-term transplantations after 24 h reperfusion as tacrolimus, with steroids for episodes of expression of ischemia reperfusion injury, AR, has been quite successful in protecting but it reaches excessively increased grafts against T cell mediated rejection. In expression levels after allogenic contrast, antibody mediated rejection transplantation in the intestinal muscular (AMR) continues to be a major problem, “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 8

Internal Medicine Review Small bowel transplantation March 2016 particularly since it is relatively insensitive Mesenteric arteriopathy, an important to corticosteroids.28 mechanism which underlies the

Successful intestine and multivisceral pathophysiology, is highly dependent on transplantation across a positive cross DSA. Complement seems to play a match have been described.29 Donor particularly important role in late specific antibody (DSA) formation in the dysfunction and chronic rejection of other serum of the recipient associated with organs, as well.

AMR is similar to other solid organ Immune Monitoring transplants. In contrast with preformed Immune monitoring is crucial after small DSA, de novo DSAs have been shown to bowel transplantation. Recipients be associated with adverse clinical experience around 50 - 75% of the AR, outcomes, mainly acute and chronic more than 10% lymphoproliferative 29 rejection. De novo DSAs seem to appear diseases due to over immune suppression in approximately one fourth of the patients and more than 10% chronic rejection after transplantation as a result of which was ended up with graft loss within alloreactive humoral responses and are 5 years after transplantation especially in associated with increased incidence of children.31 chronic rejection and graft loss. But histologic findings of AMR in SBT are not Unlike other types of transplantation, the yet well-defined due to nonspecific C4d intestine lacks a reliable and minimally staining in mucosal biopsies and absence invasive marker to predict rejection. of mesenteric arterial structures in the Protocol biopsies and histological analysis biopsies.30 AMR is not only an obstacle to remain the gold standard for allograft transplantation in presensitized recipients, monitoring, but neither is free of but DSAs are increasingly recognized as complications, especially in smaller grafts. causes of long-term chronic rejection and Up to 30% of biopsies are nondiagnostic late allograft failure.31 This recognition has and multiple biopsies may be required to 32 followed the development of new exclude rejection. Best if performed in technologies, particularly single antigen the context of auxiliary testing of tissue fluorescent (Luminex) bead assays, to and concomitant systemic biomarker detect DSAs. There is increasing evaluation. Among auxiliary assays recognition that DSA causes of late graft increasing in use are measurements of 33 loss due to dysfunction and rejection. citrulline level in the blood,

Internal Medicine Review Small bowel transplantation March 2016 cytofluorographic analysis of peripheral than 1 signifies decreased risk. The immune cell population,34 cytokine sensitivity and specificity of the test for profiling, and the quantitation of distinct detection of AR in intestine transplantation gene set changes.35 Developments in is 87.5 and 83.3%, respectively.37 understanding of genes provide promise It has been reported that miRNAs (micro that limited gene sets, taken from blood or RNA) have a critical role in immune from intestinal biopsies, will enhance regulation. The expression of 384 miRNAs pathological diagnosis and endorse the and 280 mRNAs associated with immune, morphological impression seen in the inflammatory and apoptotic pathways intestinal grafts. were comprehensively examined and the a. Biomarkers study revealed a miRNA signature 36 Dentritic cells (MDC) are potent antigen occurring during intestinal AR. These presenting cells and serve as markers for results seem to reflect an association not the recipients who are prone to AR. only with T cells but also with B-cell- Plasmacytoid CD123 (PCD) dendritic cells mediated immune responses during AR. which may have tolerogenic potential are The over expression of miR-142 and miR- known to increase during the rejection-free 223 might promote T-cell predominant posttransplant period. A single center study differentiation and mediate graft injury done with 23 children declares that the during intestinal AR. Furthermore, the children experienced AR have results established a positive association significantly higher MDCs/PDCs ratio between miRNA/mRNA pairs during compared to nonrejectors.36 The intestinal AR. The data suggested that carboxyfluorescein succinimidyl ester miRNAs have a critical role in the (CFSE) mixed leucocyte response (MLR) activation of infiltrating cells during identifies T cytotoxic cell proliferation as a intestinal AR.

marker of AR in solid organ These differences in miRNA expression transplantation. The ratio of donor and patterns can be used to identify novel third-party-induced proliferative CFSE T biomarkers and therapeutic targets for cells, which is measured by flow immunosuppressive agents. Wide cytometry, was assessed as the immune interpatient variability reduces the ability reactivity index for each subset. Immune to set cutoff points for rejection across the reactivity index of more than 1 shows normal population. Nonetheless, these increased risk of rejection and index less predictive and discriminative biological “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 10

Internal Medicine Review Small bowel transplantation March 2016 markers require further large-scale in- find out the recipients who are prone to depth studies. AR attacks. Although these markers have

Nucleotide Oligomerization Domain more than 90% sensitivity and specificity (NOD)-2, plays an important role in for predicting AR and appear as promising limiting innate immune activation. NOD2 results, routine monitoring in the clinical is a pattern recognition receptor found on setting has not been established.

macrophages, dendritic cells and paneth b. Imaging tests cells that sense bacterial products. Defects Imaging modalities like positron-emission in this sensor are thought to result in tomography, other radioactive tracers such impaired expression of intestinal as 111In-labeled platelets, radiolabelled antibacterial peptides and other defects in white cell scintigraphy, and MRI have innate immune responses, which could been investigated in terms of predicting trigger an activation of immune cells AR. But none of these techniques were through microorganism that might found to be useful due to low volume of contribute to the rejection process. It is SBT did not make possible to the therefore possible that the structural shifts interpretation of the any possible changes. observed during rejection are a result In an animal experiment, measuring rather than a cause of an exacerbated luminal fluid changes with using new immune response. Strategies that suppress modified perfusion system along with the levels of enterobacteria might therefore FITC-inulin allowed real-time determi- constitute a viable therapeutic alternative nations of fluid and/or electrolyte to improve small intestinal allograft movement along the small intestine.40 By survival. In healthy individuals, this way, it will be possible to follow-up continuous secretion of antimicrobial any intestinal dysfunction reliably. peptides by paneth cells is controlled by the intracellular bacterial recognition Laser doppler monitoring is another protein. Patients with NOD2 noninvasive monitoring method, and the polymorphisms who undergo SBT are at method allows continuous monitoring. significantly greater risk for early Monitoring by laser doppler is easy to rejection, decreased survival and death due perform and noninvasive, but the to sepsis.39 monitoring device has to be attached to the Besides biomarkers which identify ARs, intestine. The implantable doppler seems some markers have been investigated to at a glance the most ideal solution for

Internal Medicine Review Small bowel transplantation March 2016 monitoring the grafts, as it is extremely detecting differences between healthy fast and allows continuous monitoring. Yet transplants and rejection when compared even if the implantable doppler might be to absolute cell numbers by determining low in specificity, it still represents a fast the enterobacteria/total bacteria ratio. A and sensitive screening. Placement of the cut-off point of <49.7% of Firmicutes implantable doppler at the vascular pedicle would hereby discern active rejection with in an intestine can be a challenge. To 90.0% sensitivity and 90.9% specificity. obtain an early warning regarding venous Early results of stool testing for congestion, the monitoring device has to calprotectin, an S-100 protein released be placed around the vein of the transplant, from infiltrating lymphocytes, has shown and with the thin wall of the visceral veins promise for surveillance of the intestine the placement itself might induce venous graft with elevations noted in some prior to congestion. the onset of histologic changes of AR and c. Stool tests normal levels consistently associated with Stool examinations were thought to be one normal histology. The fecal content of of the predictors of AR. Recent discoveries calprotectin depends on migration of around intestinal flora in the settings of neutrophils into the intestinal lumen and various diseases may provide a viable has proven to be a sensitive marker of model for studying intestine allograft disease activity for inflammatory intestinal 42 injury with reference to alterations in the diseases. It is recommended that the gut microflora after transplantation. recipients with high levels of calprotectin Alterations in intestinal microflora have should undergo intestinal biopsy. Another already been shown in intestine transplant study showed that stool calprotectin levels recipients. During episodes of rejection, of the recipients with rejection were the proportions of phylum Firmicutes and significantly higher than the patients with the order Lactobacillales were signify- viral enteritis or normal biopsies. The cantly decreased, while those of the analysis suggested that the optimal cutoff phylum Proteobacteria, especially the level to distinguish rejection from other family Enterobacteriaceae, were signify- diagnosis is 92mg/kg with sensitivity of 43 cantly increased. So, especially Firmicutes, 83% and specificity of 77%. Another could be used to discriminate between suggested predictor is IGF-1. During nonrejection and active rejection.41 The episodes of intestinal dysfunction analysis showed an improvement in calprotectin levels significantly increase “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 12

Internal Medicine Review Small bowel transplantation March 2016 and IGF-1 levels decrease.53 In the patients by regulating propulsive intestinal motility with low IGF-1 levels and high in the initial absence of extrinsic signaling. calprotectin should have enteral feeding Local inflammatory and immunological interrupted and put back on TPN till cause changes in the tunica muscularis of of high calprotectin is determined. transplanted intestines also result in dysmotility, both after ischemia/ Citrulline is a protein released from reperfusion injury and during rejection. So, enterocytes which the levels show negative dysmotility can be one of the predictors of correlation with the function of the small acute rejection.45 bowel graft.33 From its enterocyte specific origin it first gained interest in intestinal Bile acid analysis, serum gentamicin failure as a marker. Although diminishing levels, Granzyme B and perforin analysis, in plasma levels of citrulline appear to be proinflammatory mediator leukotriene E4, associated with mucosal damage, it does vitamins B2, B5 and B6 were tested as not reliably predict rejection. In a recent markers of rejection after small bowel study, citrulline was assessed as marker of transplantation, but none of these were the patient with wide variety of intestinal found to be sufficiently reliable.46

pathology and lack of predictor of Immune suppressive therapy rejection.44 Several strategies and immunosuppressive

27 The fecal content of alpha-1 antitrypsin regimens were utilized in SBT. Best can be used as a marker for loss of plasma results were obtained with induction proteins to the gastrointestinal lumen. therapy with anti-lymphocyte antibodies, Increased losses into feces can be caused monoclonal or polyclonal, being used in 7,27 by inflammatory diseases leading to most centers. The most commonly used enhanced vascular wall permeability, gut drugs for induction are thymoglobulin, erosions causing loss of interstitial fluid, alemtuzumab, basiliximab and increased venous pressure, and lymphatic daclizumab. obstruction.44 The maintenance immune suppression d. Other predictors with tacrolimus is carried out; keeping the Motility of the transplanted intestine is first month levels 12 to 15 ng/ml and crucial for transplant outcome. The reduced to 12 to 8 ng/mL after this initial 10 interstitial cells of Cajal, with their period. As in the other abdominal organ pacemaker function, play an important role transplants, cortico-steroids are also used,

Internal Medicine Review Small bowel transplantation March 2016 and removed in accordance with the type growth factor-I. Each of these factors has of grafts and preference of each center. previously been described as facilitating intestinal mucosa repair, either through Although improvements in immune enhancement of cell proliferation or suppressants have resulted in better control inhibition of epithelial cell apoptosis, or by of rejection after SBT, the incidence of a combination of both. Some beneficial rejection remains high, with rates of acute effects of BMMSC transplantation with and chronic rejection after SBT. So, some SBT were shown in the clinical settings.47 novel attempts are examined in SBT, like bone marrow mesenchymal stem cell Tissue engineering (BMMSC) transplantation in addition to Although still in experimental phases, SBT.47,48 Bone marrow mesenchymal stem recent developments in identification and cells (BMMSCs) have shown immune- propagation of small bowel stem cells and suppressive activity in transplantation. advances in tissue engineering promise BMMSCs are able to inhibit immunologic that realistic alternatives to the deceased refractory cells attacking transplanted donors can be seen in the future. In the organs and have the ability to enhance or animal model, short segments of small maintain the re-epithelization process of bowel which were manufactured by small intestinal epithelium. In an animal seeding intestine stem cell organoids onto study, infusion of BMMSCs suppressed collagen scaffolds demonstrated improved AR in SBT, and that the immune growth after placing in continuity with regulatory effect of these cells were found remnant bowel surgically compared to to be due to the balance of Th1/Th2, control animals without tissue engineered 49 Th17/Treg, and their related cytokines and bowel. These kinds of developments NK cell activity, as well as Treg suggest that the future efforts may be expansion.48 Chimerism and tolerogenic targeted more toward repair of injured regiments that induce Tregs and prevent bowel or growth of new intestine tissues the development of DSA are important from autologous stem cells. treatment goals for the future. Recent CONCLUSION studies have documented BMMSC As a conclusion of these developments, synthesis and the release of several morbidity and mortality rates of small cytokines and growth factors such as, bowel transplantation have decreased, interleukin-11, hepatocyte growth factor, lately. As the experience of the centers fibroblast growth factor-2 and insulin-like increase and the mechanism of immune “Copyright 2016 Internal Medicine Review. All Rights Reserved.” 14

Internal Medicine Review Small bowel transplantation March 2016 alloreactivity are elucidated, authors' belief dependent short bowel syndrome of is that the success in this field will be infancy. J Pediatr. 2010;156(4):580-5. enhanced. Stem cell transplantation and tissue engineering are seen as promising 6. Berney T, Kato T, Nishida S, et al. procedures for the future. Portal versus systemic drainage of small bowel allografts: comparative REFERENCES assessment of survival, function, 1. Grant D, Abu-Elmagd K, Mazariegos rejection, and bacterial translocation.J G, et al. Intestinal transplant registry Am Coll Surg. 2002 ;195(6):804-13. report: global activity and trends.; Intestinal Transplant Association. Am 7. Fryer JP. The current status of J Transplant. 2015 ;15(1):210-9. intestinal transplantation. Curr Opin Organ Transplant 2008;13(3):266-72 2. Gotthardt DN, Gauss A, Zech U, et al. Indications for intestinal 8. Kato T, Selvaggi, Gaynor JJ, et al. transplantation: recognizing the scope Inclusion of donor colon and ileocecal and limits of total parenteral nutrition. valve in intestinal transplantation. Clin Transplant. 2013;27 Suppl 25:49- Transplantation 2008 ;86(2): 293-297. 55. 9. Suzuki H, Li XH, Miyamoto M, Sano 3. Abu-Elmagd KM. The small bowel T, Hattori Y, Yamashita A. Induction contained allografts: existing and of transplantation tolerance in adult proposed nomenclature. Am J rats by vascularized spleen Transplant. 2011;11(1):184-5. transplantation. Transplantation. 1997;64(4):650-4. 4. Smith JM, Skeans MA, Horslen SP, et al. OPTN/SRTR 2013 Annual Data 10. Kato T, Tzakis AG, Selvaggi G, et al. Report: intestine. Am J Transplant. Transplantation of the spleen: effect of 2015;15 Suppl 2:1-16. splenic allograft in human multivisceral transplantation. Ann 5. Kaufman SS, Pehlivanova M, Surg. 2007;246(3):436-44; discussion Fennelly EM, et al. Predicting liver 445-6. failure in parenteral nutrition-

Internal Medicine Review Small bowel transplantation March 2016

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Internal Medicine Review Small bowel transplantation March 2016

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Figure 1. Isolated intestinal graft

Figure 2. Mesenteric venous and arterial anastomosis of the small intestinal graft