Curr Gastroenterol Rep (2015) 17: 5 DOI 10.1007/s11894-014-0427-8

SMALL INTESTINE (J SELLIN, SECTION EDITOR)

Intestine and Multivisceral Transplantation: Current Status and Future Directions Chandrashekhar A. Kubal & Richard S. Mangus & A. Joseph Tector

Published online: 23 January 2015 # Springer Science+Business Media New York 2015

Abstract Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slowgrowing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.

Keywords Intestinal failure . Intestine transplantation . Liver failure . Multivisceral transplantation . Parenteral nutrition . Acute rejection . Chronic rejection . Immunosuppression

This article is part of the Topical Collection on Small Intestine C. A. Kubal (*) : R. S. Mangus : A. J. Tector Transplant Division, Department of Surgery, Indiana University School of Medicine, 550 N University Blvd, Room 4601, Indianapolis, IN 46202-5250, USA e-mail: [email protected]

Introduction Animal models of intestine and multi-visceral transplantation were first described by Lillehei and Starzl in 1960 [1, 2]. Attempts on intestine transplantation in human were then made, but were defeated by rejection, sepsis, and technical complications [3–5]. Following early transplantation attempts, deaths were most commonly a consequence of acute graft rejection and subsequent sepsis-associated multi-organ failure [5, 6]. The introduction of ciclosporin in 1978 by Calne and colleagues [7] rejuvenated interest in intestine transplantation; in 1988, Grant et al. [8] reported a patient receiving combined liver and intestine transplantation that remained alive 1 year after the transplant. The introduction of tacrolimus, a potent new calcineurin inhibitor, marked the next major step in allowing clinical intestine transplantation to become a reality. In North America, a total of 2411 intestine and liverintestine transplants have been performed since 1990. Since 2001, more than 100 transplants are performed each year, which peaked at 198 in 2007 [www.OPTN.org]. In the last two decades, intestine transplantation has evolved significantly and is now considered to be the standard of care for selected patients with intestinal failure [IF] [9, 10]. Intestine transplantation may be performed in isolation, with a liver transplant, or as part of a multivisceral transplant including the liver, stomach, pancreas, and colon. Posttransplant graft and patient survival have improved over the past decade, and the number of recipients alive with a functioning intestinal graft has steadily increased [11]. Encouraged by this success, intestine transplantation, particularly in combination with liver transplant is now being offered to patients with diseases other than IF. In this manuscript, recent and important studies around intestine and multivisceral transplantation have been reviewed.

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Indications (Table 1) Intestinal Failure

Curr Gastroenterol Rep (2015) 17: 5 Table 1 Characteristics of patients on intestine/multivisceral transplant waiting lists in 2002 and 2012 (source: OPTN/SRTR 2012 Annual Data Report: Intestine) [85] 2002

Inability of the intestinal tract to maintain adequate nutritional status, hydration, and electrolyte balance is considered as IF. This results from a loss or absence of sufficient absorptive surface area or absorptive function of intestine. IF remains to be the commonest indication for intestine transplantation. Acute or chronic loss of the enteric absorptive mass caused by short gut syndrome, intestinal dysmotility, or enterocyte dysfunction can precipitate IF, regardless of intestinal length. In many conditions, the available enterocyte mass is inadequate to provide the body with sufficient nutrition or hydration. The most common causes of IF in children are necrotizing enterocolitis, gastroschisis, intestinal atresia, volvulus, severe extensive motility disorders including subtotal aganglionosis, chronic intestinal pseudoobstruction syndrome, and congenital diseases of enterocyte development. In the adult population, ischemia, inflammatory bowel diseases, pseudo-obstruction, trauma, massive surgical bowel resection, and tumors are the common causes of IF. Despite recent advances in the management of IF, these patients carry a high burden of morbidity and mortality. In the absence of sufficient intestinal adaptation, many patients remain dependent on long-term parenteral nutrition [PN], which is costly, invasive, and associated with complications. Mortality estimates for the IF population are high [12, 13]. It has been reported that the majority of patients relying on PN for more than 5 years will develop significant liver disease [14]. Additionally, PN carries a substantial cost burden. Per patient, mean annual reimbursements to healthcare professionals have been reported to range from $100,000 to $250,000, with reimbursement for PN-related hospitalizations ranging from $10,000 to $196,000 and costs for supplies and infusion solutions ranging from $75,000 to $122,000 [15]. For these reasons, in parallel with the medical and surgical advancements in the management of patients with IF, intestine transplantation will remain as an important therapeutic option. Currently, intestine transplantation is considered for patients in whom intestinal rehabilitation attempts have failed and who are at risk of life-threatening complications of PN. In fact, it has been shown that patients awaiting intestine-only transplant have higher survival compared with that in patients waiting for combined intestine-liver transplant. Therefore, referral of appropriate patients for intestine transplantation before the development of advanced liver disease is critical to enhancing patient outcomes [16]. The US Centers for Medicare and Medicaid Services (CMS) approved intestine transplantation for patients with irreversible IF- and PN-related complications in 2000 [17]. The CMS definition of PN failure includes the following:

2012

n=176

%

n=252

%

Age

65

92 38 15 25 5 1

52 22 8 14 3 1

107 50 20 30 40 5

42 20 8 12 16 2

Gender

Female Male While Black Hispanic Asian Other/ unknown Necrotizing enterocolitis Congenital SGS Other SGS Pseudoobstruction Enteropathies Other/ unknown Liver-intestine Intestine alone

108 68 126 26 19 4 1 24

61 39 71 15 11 2 1 14

134 118 150 46 42 8 6 30

53 47 60 18 17 3 2 12

46 49 9 1 47 83 93

26 28 5 1 27 47 53

39 86 15 2 80 96 156

15 34 6 1 32 38 62

Race

Primary disease

Type of transplant

Characteristics of patients on intestine transplant waiting list: Majority of the transplant recipients are children, other/unknown indications include portomesenteric thrombosis, nuroendocrine and slow-growing tumors, abdominal catastrophes, etc. SGS short gut syndrome

& & & &

Presence of PN-associated liver disease Loss of central venous access (loss of three to six central venous access sites in children or two to four central venous access sites in adults) Recurrent catheter-related sepsis or a single episode of fungal sepsis Recurrent bouts of severe dehydration or metabolic abnormalities

Other Indications Considering its success, intestine transplantation, particularly in combination with liver, pancreas, and stomach (also referred as multivisceral transplant), is being offered to patients with other indications [16]. Some of the major categories of such indications are as follows:

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Abdominal Catastrophes The management of patients with a history of multiple surgeries, radiation enteritis, severe abdominal trauma, or multiple enterocutaneous fistulae can be challenging. These patients have often exhausted all surgical options, and are on long-term PN and have poor quality of life. In select patients with such a complex surgical abdomen, normal anatomy and physiology can be restored by intestine transplantation with or without inclusion of the liver, pancreas, and stomach [16]. Slow-Growing and Neuroendocrine Tumors Large intraabdominal desmoid tumors and gastrointestinal stromal tumors tend to invade locally, especially to the mesenteric root and can cause vascular compromise to abdominal viscera. Such patients often undergo multiple small-bowel resections and are rendered short gut on PN. The role of intestine and multivisceral transplantation for patients with complicated abdominal desmoid tumors, in whom attempts of surgical resection and intestinal rehabilitation have failed, is evolving. Complete resection followed by multivisceral transplantation could be a therapeutic option for these advanced tumors. Several reports indicate excellent long-term survival and no recurrence of such tumors following intestine/multivisceral transplantation [18–21]. Recently, multivisceral transplantation is being considered as a therapeutic option for select cases of neuroendocrine tumors with liver metastases that are minimally responsive to chemotherapy and radiation therapy. While long-term results are awaited, some reports indicate that in the absence of extra abdominal disease, especially based on 68-galliumbased imaging, these transplants can be potentially curative with minimal recurrence [22]. Complete Porto Mesenteric Thrombosis When complete thrombosis of the splanchnic venous system coexists in patients with cirrhosis, particularly in the absence of a large tributary for anastomosis to the donor portal vein, liver transplantation may not be a viable option. Alternative vascular reconstructions such as cavoportal hemitransposition, renoportal vein graft interposition, and utilization of the hepatic artery for portal flow have been proposed [23, 24]. However, these techniques are not able to decompress the mesenteric venous system completely and portal hypertension and its complications continue to exist after liver transplantation. Multivisceral transplantation is the only option which completely replaces the portomesenteric system to correct the primary problem and relieve the portal hypertension [25].

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donor intestine transplants have been reported [26, 27]. In the case of isolated intestine transplantation, there are few patients on the waiting list in the USA in comparison with the cadaver donor pool for intestine grafts. However, patients requiring combined liver and intestine transplants compete with the liver transplant waiting list and consequently have high wait list mortality. In 2013, the UNOS Liver and Intestinal Transplantation Committee revised the organ allocation policy in order to reduce high wait-list mortality for liver-intestine transplantation. The committee gave a priority in the allocation system above the current model for end-stage liver disease (MELD) allocation for recipients awaiting liver-intestine transplantation [11].

Surgical Anatomy Choice of transplant graft is made on a case-by-case basis depending on the patient’s anatomy and disease process. The four main types of intestine transplantation [18] are as follows: 1. Isolated intestine transplant with or without portion of colon: This type of transplant is performed in IF patients with preserved liver, stomach and pancreas function. 2. Liver-intestine transplant: This transplant is usually indicated for patients with IF, who have developed end-stage liver failure due to the long-term PN. 3. Multivisceral transplant: This type of transplant is indicated in patients with IF and liver failure wherein liverintestine transplant is not possible due to complex abdominal pathology. The composite allograft includes the pancreaticoduodenal complex along with liver and small bowel with or without a portion of colon. Patients with concomitant liver failure and portomesenteric thrombosis or with slow-growing tumors also benefit from this procedure. 4. Modified multivisceral transplant: This transplant type includes the pancreaticoduodenal complex along with small bowel with or without a portion of colon. In patients with preserved liver function and concomitant pancreatic insufficiency with IF, such as patients with cystic fibrosis, chronic pancreatitis, or type 1 diabetes mellitus, a composite small-bowel-pancreas graft may be considered. Patients with intestinal pseudo-obstruction with concomitant severe gastroparesis are also considered suitable candidates for this type of transplant.

Immunology Organ Allocation For the most part, intestine and multivisceral transplantation mainly utilizes deceased donor organs, although some living

Acute rejection (AR) and chronic rejection (CR) remain major impediments to long-term graft and patient survival, and better understanding of the immunopathology of intestine

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transplantation may lead to improved outcomes. AR can range from mild to severe. In severe form there can be complete loss of mucosa, also called as exfoliative rejection. Cell-Mediated Immunity The significant allogeneic cellular load presented by the intestine/ multivisceral allograft is strongly immunogenic and can initiate host effector immune response or can dominate the host and cause graft versus host disease (GVHD). Both situations demand for the use of potent immunosuppression. It has been shown that by week 10 posttransplantation, the intestine becomes populated with lymphocytes from the host and a chimera is created with donor epithelium, intestinal matrix and vasculature, and host inflammatory cells [28]. Thus, the presence of recipient lymphocytes within intestinal submucosa may not necessarily indicate a process of rejection. The cellular mechanisms of rejection, particularly that of early exfoliative rejection, despite heavy induction immunosuppression in intestine and multivisceral transplantation remain unclear. Nonetheless, the incidence of AR [29] and GVHD [30] remain high after intestine and multivisceral transplantation. Humoral Immunity Intestine transplant recipients are mainly matched to suitable donors on the basis of ABO blood type. The characterization of antibody-mediated rejection in the presence of preformed donor-specific antibodies (DSAs) [31, 32] has led to the routine use of cross-match tests in all of solid organ transplantation [33]. Concerns of potential antibody-mediated rejection have led some clinicians to implement strategies to desensitize recipients with preformed antibodies [34, 35]. The deleterious effects of preformed DSA are however not prohibitive in the setting of intestine and multivisceral transplantation, and successful intestine and multivisceral transplantation across a positive crossmatch have been described before [36, 37]. In our experience, preformed DSAs were not associated with increased AR, CR, or graft loss due to rejection [38]. In contrast with preformed DSA, DSAs appearing after transplantation [de novo DSA] have been shown to be associated with adverse clinical outcomes, mainly acute and chronic rejection [36, 39]. De novo DSAs seem to appear in approximately one fourth of the patients after transplantation as a result of allo reactive humoral responses and are associated with increased incidence of CR and graft loss [36, 40]. Protective Effect of the Liver The incidence of AR of intestine component of multivisceral or liver inclusive transplants is lower than that in intestine transplantation [41–44]. The exact mechanism behind this observation remains unknown; however, several hypotheses have been postulated [45, 46].

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Complications and Concerns Two major concerns for any patient after intestine or multivisceral transplantation are infections and rejection of the graft. With exfoliative rejection of transplant intestine, there is sloughing of the intestinal mucosa, which in turn results in the loss of physical barrier between fecal microbes and circulation. Translocations of bacteria and fungi are common in this setting. Acute Rejection Despite the use of potent immunosuppression, AR remains a major problem in patients receiving intestine and multivisceral transplantation. The incidence of AR varies in different studies, more or less occurring in half of the patients receiving intestine transplantation [47]. With the use of antibody induction immunosuppression, a fall in AR incidence is observed in some series [48]. The onset of AR is typically within 3 months after transplantation, but late AR also occurs, particularly in association with lowered immunosuppression or non-compliance [49]. In patients with exfoliative rejection, the intestinal epithelium is denuded as observed on endoscopy. On histological evaluation, there is loss of epithelial surface with the formation of granulation tissue. A retrospective analysis found 15 % incidence of exfoliative rejection at a median time of 22 days after intestine transplantation with high incidence of graft loss (93 %) and death (69 %) [50]. The diagnosis of AR is made with a combination of clinical observation, endoscopic examination, and the analysis of mucosal biopsies. In 2003, in an attempt to standardize grading of intestine transplant biopsies, an international group of pathologists and clinicians at the Eighth International Small Intestinal Transplantation Symposium proposed a unified grading system for AR in endoscopically derived smallintestine allograft biopsy samples [51]. The grading scheme has been adopted by multiple centers and has been validated retrospectively [47]. The histologic diagnosis of AR is based on a varying combination of the following: (1) infiltration by a mixed but primarily mononuclear inflammatory population including blastic or activated lymphocytes; (2) crypt injury (characterized by cytoplasmic basophilia, nuclear enlargement, and hyperchromasia, decreased cell height and mucin depletion) and inflammation; and (3) increase in crypt apoptotic bodies. Crypt cell apoptosis is a physiologic process of regulation of the intestinal epithelium, which occurs extensively in AR. Although a common feature of rejection, increased crypt cell apoptosis is also seen presence of protozoal or viral infections [52, 53] or is associated with the use of the immunosuppressant mycophenolate mofetil [54]. In addition to histologic assessment, attention should be paid to the endoscopic findings, which provides an overall estimation of distribution and magnitude of mucosal injury. Molecular biomarkers and other laboratory analyses are rapidly evolving in

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identifying and further characterizing the rejection process and may be utilized in clinical practice in the future [55]. Infections As mentioned before, infections are common in intestine or multivisceral transplant recipients. In a report of pediatric patients who had had intestine transplants, the infection rate was 91 %, with a median of five infections per child [56]. In another report, within the first year post-intestine transplant, patients carried a 90–100 % risk of bacterial infection, a 15–30 % risk of cytomegalovirus [CMV] infection, and a 30–50 % risk of fungal infection [57]. Compared to multivisceral transplant recipients, intestine alone recipients are at a much higher risk of blood stream infections and fungal infections. Essentially, almost all patients experience at least one infection following transplantation [58]. CMV is particularly a problem in intestine transplantation recipients because more than half the donor population is CMV positive [59]; in this setting, latent lymphotrophic virus is transmitted to an immunosuppressed host in a lymph-rich organ [60]. Although it is ideal to avoid CMV-positive donor to CMV-negative recipient transplants, this option is not always available due to a high percentage of CMV-positive donors. To counter this risk, CMV prophylaxis with ganciclovir and CMV immune globulin (CytoGam®) is utilized in most centers [61]. Reassuringly, studies have shown that the use of CMV-positive donors for intestine and multivisceral transplantation did not increase the incidence of CMV disease [60]. Other major post-transplant complications include posttransplant lympho-proliferative disease [PTLD], GVHD, CR, and chronic kidney disease. PTLD, often driven by Epstein-Barr virus [EBV], is common in pediatric recipients and also in recipients of isolated intestine transplants in comparison with multivisceral transplants [62]. With improved monitoring and early detection of EBV, the incidence of PTLD is declining [63]. For patients who underwent transplant from 2006 to 2010, the incidence of PTLD among EBVnegative recipients was 6 % at 1 year, 7 % at 2 years, 9 % at 3 years, and 11 % at 5 years [11]. The incidence of GVHD is less than 10 % and is common after multivisceral in comparison with intestine alone transplantation. In most cases, GVHD involves skin and can be treated with steroids. When extensive, involving recipient bone marrow, GVHD is associated with high morbidity and mortality [56, 64]. With improving early and long-term survival outcomes, CR has become apparent. It is an important cause of graft loss, affecting up to 15 % grafts reported in a large series by Abu-Elmagd et al. [65]. Patients with chronic rejection present with diarrhea, protein-losing enteropathy, weight loss, and chronic abdominal pain. Explant intestine allograft specimens show a matted organ with transmural thickening, flattened mucosal surface, and intermittent ulcerations. The pathological changes of chronic rejection are seen in the deeper layers of the gut wall and in its vasculature, with relative mucosal sparing and

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chronic allograft vasculopathy [66]. As with other transplants, chronic kidney disease is a common complication after intestine transplantation, related to the chronic use of the calcineurin inhibitors and dehydration from not having colonic absorption of water.

Post-transplant Management Well-organized post-transplant management of intestine or multivisceral transplantation recipients is the key to successful outcomes. It is imperative to anticipate and prevent complications in these patients. Historically, transplant intestine has been considered to be highly immunogenic and therefore, most centers use relatively heavy immunosuppression in comparison with other solid organ transplants. With such immunosuppression, cell-mediated rejection has decreased to some extent; however, the patients are more likely to experience infections. Therefore, it is important to maintain steady levels of immunosuppression with surveillance of allografts for rejection. Mild episodes of AR, when detected early, can be managed with steroids with success in most instances. The lack of a suitable biomarker reflective of allograft health is a problem. Common viral infections include CMV and EBV. To prevent these, strategic surveillance and prophylaxis is important. Most centers utilize ganciclovir prophylaxis with or without CMV immune globulin [61]. Presence of EBV viremia may be a significant risk factor for the development of PTLD in these patients, and may reflect a more severely immunosuppressed state [67]. To prevent devastating complications associated with PTLD, frequent measurement of EBV viral load and adjustment of immunosuppression is necessary. Hypogammaglobulinemia is common after intestine transplantation [68], and severe hypogammaglobulinemia may have an adverse impact on infection-related morbidity and mortality [69, 70]. Thus, patients at high risk for infection would benefit monitoring of IgG levels and pre-emptive treatment with intravenous immunoglobulins. As AR is common in these patients, aggressive surveillance and management is important to patient survival. Again, it is most beneficial to detect AR at an early stage. When patients present with severe AR, most centers use biologic induction agents such as anti-thymocyte globulin and alemtuzumab to reverse it. Sepsis is common in patients with severe rejection that leads to loss of the mucosal barrier with consequent exposure to intraluminal pathogens. During rejection episodes, patients are generally placed on PN. Recovery from severe rejection can require several weeks to months; however, full recovery is possible and patients can return to normal intestinal function. It is important to identify worsening severe rejection by clinical observation and serial

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endoscopic evaluation, wherein the allograft develops ischemic changes. In such instances, emergent removal of the intestine graft is necessary. The patient may recover after removal of the allograft and withdrawal of immunosuppression and may be re-transplanted at a later date. Severe rejection may be associated with fibrosis and scarring of transplant intestine, which affects long-term absorptive function and may result in CR.

Immunosuppression The goal of current immunosuppressive regimens is to balance prevention of rejection episodes while minimizing the adverse effects and morbidity associated with the immunosuppression itself. Most centers use two or three agents for maintenance immunosuppression, consisting of a calcineurin inhibitor (mostly tacrolimus), corticosteroid, and an antiproliferative agent (either azathioprine or mycophenolate mofetil [MMF]) [43, 71–74]. The use of induction agents (antilymphocyte globulin, alemtuzumab, cyclophosphamide, or OKT3) is variable [43, 71, 74, 75]. Sirolimus (mTOR inhibitor) has been tried as an alternative to calcineurin inhibitors [76–78]; however, this class of drugs is avoided immediately after transplantation due to associated wound healing complications. Recently, interleukin-2 receptor antagonists have been used as induction agents, as well as for maintenance immunosuppression [38, 79, 80].

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incorporate the initial experience in this field and significant advances have since been attained. Recurrence of the primary disease, such as inflammatory bowel disease, is rare in the transplanted intestine. However, intestinal failure can occur as a result of loss of absorptive capacity of the intestinal mucosa after exfoliative rejection and chronic rejection. Recurrence of dysmotility in transplant intestine has been seen, and overall motility of the transplant intestine in humans remains to be well characterized. Recurrence of slow-growing tumors and neuroendocrine tumors after multivisceral transplantation is uncommon and, when it occurs, can be managed with radiation and or surgical resection. A comprehensive long-term study on nutritional outcomes in pediatric recipients by Venick et al demonstrated positive growth and weight gain. Some micronutrient deficiencies such as zinc, iron, and copper are common, and absence of rejection is associated with weight gain and growth [84]. Several studies have assessed quality of life (QOL) after intestine or multivisceral transplantation in pediatric and adult recipients. The most comprehensive study by Abu-Elmagd et al assessing different multidimensional psychosocial, emotional, and physical QOL measures in a large series demonstrated that despite the co-existence or development of neuropsychiatric disorders, most survivors were reintegrated to society with self-sustained socioeconomic status. Psychological, emotional, and social QOL measures significantly improved after transplantation [10].

Outcomes Conclusions Patient survival after intestine or multivisceral transplantation has steadily improved over the past decade [11]. For intestine/ multivisceral transplant recipients in 2005–2007, the 1-, 3-, and 5-year patient survival was 78, 66, and 63 %, respectively [11]. Considering both recipient age and organs transplanted, adult recipients of intestine transplants have the best 1-year graft survival (80 %), and pediatric recipients of intestine-liver transplants have the best 5-year graft survival (56 %). It has become clear that after the initial period of increased risk, the survivors have excellent long-term outcomes including quality of life. In a recent publication, Abu-Elmagd et al reported conditional patient survival in patients that survived beyond 5 years to be 75 % at 10 years and 61 % at 15 years after intestine or multivisceral transplantation [10]. Pre-transplant comorbidities, hospitalization at the time of transplant, renal function, age, antibody induction immunosuppression, and the presence of donor specific antibodies impact survival outcomes [81–83]. Despite improvements in short-term outcomes, overall patient survival at 10 and 15 years remains modest at 42 and 35 %, respectively [65]. These data however need to be interpreted with caution as most of the large studies

Intestine transplantation is now considered to be the standard of care for patients with IF that have failed intestinal rehabilitation and are at risk of complications from long term PN. In large-volume centers, the indications for intestine or multivisceral transplantation have expanded to include patients with dis eases such as complete portomesenteric thrombosis with cirrhosis, neuroendocrine and slow-growing tumors, and abdominal catastrophe. Despite recent improvement, the outcomes after intestine or multivisceral transplantation are still not comparable to that after other solid organ transplants. The major impediments to improved outcomes are acute and chronic rejection, infections, and adverse effects of potent immunosuppression. Further understanding of mechanisms involved in the immunologic processes, alterations of intestinal microbiome, and mucosal immunity may improve outcomes. Regardless, intestine transplantation remains the only option for patients with IF with complications of PN, and in such patients, early referral and transplantation may be life saving.

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Future Directions

References

The improvement in outcomes seen over the past decade, along with expanding indications, may contribute to significant growth of intestine/multivisceral transplantation. There are no randomized clinical trials comparing intestine transplantation to long-term PN to establish guidelines. Late referrals are a problem for patients, as it has direct impact on posttransplant outcomes. Early referral for isolated intestine transplantation will reduce the need for combined liver-intestine or multivisceral transplants, thereby increasing organ availability for those in need of liver transplantation. The lack of completely safe PN in combination with further improvement in intestine transplant outcomes, a wider application of preemptive intestine transplantation, can be justified for patients with IF before complications occur. To improve outcomes, it is essential to understand mechanisms involved in acute and chronic allograft injury. Early exfoliative rejection is a particular problem after intestine transplantation, occurring as early as 3 weeks after transplantation. At this stage, affected patients are heavily immunosuppressed and it is unlikely that this pathology is a result of lack of immunosuppression. The mechanisms involved are unclear and need to be characterized. Recent discoveries around intestinal microbiome in the settings of various diseases may provide a viable model for studying intestine allograft injury with reference to alterations in the gut microflora after transplantation. Alterations in intestinal microflora have already been shown in intestine transplant recipients. Inclusion of colon and ileocecal valve may help water reabsorption and prevent kidney failure and other associated complications from excessive diarrhea in these patients. Furthermore, strategies to encourage tolerance and allow less potent immunosuppression will be important to reduce the incidence of infections. Bidirectional immune interactions between host and intestine allograft, posing challenges otherwise, may be exploited to achieve tolerance. Large load of transferring passenger donor leucocytes in intestine or multivisceral transplants is a natural model of tolerance that has been experimented in less leucocyte-endowed organs such as in kidney transplantation by infusion of donor bone marrow cells. Additionally, strategies based on adoptive cellular therapies to generate tolerance by promoting the differentiation of regulatory T cells or extrinsic cell therapy may achieve peripheral tolerance.

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Compliance with Ethics Guidelines Conflict of Interest Chandrashekhar A. Kubal, Richard S. Mangus, and A. Joseph Tector declare that they have no conflict of interest. Human and Animal Rights and Informed Consent Human studies were done by the authors (but no animal studies). This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

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Intestine and multivisceral transplantation: current status and future directions.

Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine...
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