Present state of intestinal transplantation in Japan.

INTRODUCTION: Intestinal transplantation (ITx) is the ultimate treatment for intestinal failure (IF). In Japan, most cases of IF are a result of pediatric disease, including secondary or congenital intestinal disease or allied disorders of Hirschsprung's disease. Here, we report the results of the Japanese ITx registry. METHODS: A web-based survey form was completed. We investigated the number, age, sex, indication, surgical procedure, immunosuppressants, postoperative course, and the effects of transplantation in patients who underwent cadaveric or living-donor ITx. RESULTS: By the end of 2022, 42 cases of ITx have been performed in 38 patients in Japan. The donor sources included cadavers (29 cases) and living donors (13 cases). The surgical method was isolated ITx (N = 40) and combined liver and ITx (n = 2). Survival rates were 92%, 73%, and 59% at 1 year, 5 years, and 10 years, respectively. Ninety percent of patients completely discontinued parenteral nutrition. Approximately 80% of the patients had a performance status of 1 or less, indicating that the QOL of patients after ITx was extremely good. CONCLUSION: The results of ITx are acceptable to treat IF patients and the QOL after transplantation is also good.

Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study.

BACKGROUND: Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS: Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS: Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION: Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.

Normothermic extracorporeal membrane oxygenation support: Improving the function of intestinal grafts obtained from cardiac death donors.

Extracorporeal membrane oxygenation (ECMO) could ameliorate the energy status and viability of bowel grafts from cardiac death donors. However, the function of these grafts after transplantation is not clear. The purpose of the study was to evaluate the early function of intestinal grafts after transplantation from expected cardiac death donors supported with normothermic extracorporeal support using a porcine allogeneic orthotopic segmental small bowel transplantation model. Eighteen domestic crossbred donor pigs were assigned to living donation (LD), donation after cardiac death (DCD), and ECMO groups. In the LD group, small bowels were harvested and preserved immediately in cold storage. In the other two groups, the donor pigs received conventional rapid recovery treatment or 1-hour normothermic extracorporeal support after 10-minutes expected cardiac arrest. Subsequently, the small bowels were removed and preserved in cold storage. After 5-6 hours of preservation, small bowel grafts were transplanted into the recipient pigs that underwent enterectomy. The pathology and electron microscopy results, cell apoptosis rate, tight junction protein expression level in the intestinal mucosa, and plasma endotoxin level were evaluated after transplantation. All grafts functioned on the basis of the maltose absorption test results at day 7 after transplantation. There were no significant differences in the morphological changes in the intestinal mucosa among the three groups at day 7 after transplantation. The cell apoptosis rate and plasma endotoxin level in the ECMO group did not differ significantly than those in the LD group, but were evidently lower than those in the DCD group (P < .001). The intestinal absorptive function improved significantly in the ECMO group in contrast with that in the DCD group (P < .001). Short-term ECMO intervention can alleviate ischemia-reperfusion injuries in intestinal grafts and improve intestinal absorptive function in the early stage after transplantation. Reducing caspase-3 protein expression and cell apoptosis in the intestinal mucosa may be one of the protective mechanisms of ECMO intervention.

Successful long-term outcome after combined hematopoietic stem cell transplantation and small bowel transplantation: A case report and review of the literature.

Combining HSCT with SOT is an unusual and challenging undertaking given the complexities of immune modulation, the need to balance comorbidities, and the cumulative potential for complications. Early life-threatening complications include infections and related effects, graft rejection, and GVHD can be expected to be increased especially if the HSCT is indicated for high-risk cases such as individuals with severe combined immune deficiency and SOT that includes an intestine graft. Herein, we report such a case. Our patient is unique as a long-term survivor. We review the literature and the features of our case, especially the timing of transplants and human leukocyte antigen matching for HSCT that resulted in a successful outcome and discuss how this may be applied to others in the future.

Reoperative Surgery in Complex Crohn's Disease.

This article provides a structured approach to the technical aspects of reoperative surgery for Crohn's disease. Specific indications for surgery including repeat ileocolic resection, Crohn's complications of ileal pouch anal anastomosis and continent ileostomy, completion proctectomy, and the role of small bowel transplant will be discussed.

Comparable outcomes in intestinal retransplantation: Single-center cohort study.

BACKGROUND: Graft loss in intestinal transplantation (ITx) is close to 25% in the first year and 50% at 5-year post-transplantation. Although technically and immunologically challenging, intestinal retransplantation is now the 4th most common indication for ITx. METHODS: The aim of this study was to review and compare the outcomes of intestinal retransplantation with primary ITx, which included isolated ITx, modified multivisceral transplantation (mMVTx), and full MVTx, between 2003 and 2014 at Indiana University. RESULTS: Of 218 ITx, 18 (8.3%) were retransplantation. Causes of graft loss were rejection(78%), pancreatitis (11%), and severe intestine dismotility (11%). MVTx (16/18, 89%) was the preferred retransplantation option. In 7 (39%) patients, graftectomy was performed between primary and intestinal retransplantation. Median interval between primary ITx and retransplantation was 421 days. Although patient and graft survival rates at 1 year, 3 years, and 5 years were comparable between primary and retransplants, the number of retransplants was limited in the follow-up after post-transplant year 3. CONCLUSIONS: We identified that timing of retransplantation, graftectomy prior to retransplant allowing an immunosuppression free state, inclusion of the liver, and preserved renal function are important factors in the consideration of intestinal retransplantation. Immunological aspects remain challenging in the decision making and for short- and long-term outcomes.

The optimal intestinal segment length for experimental size-mismatched intestinal transplantation: Defining the maximum length with the lowest blood flow needs in a porcine model.

Transplanted Intestinal Segments (IS) must match the perfusion capacities of the recipient. This can be challenging during a size-mismatched SBTX. In this study, we defined the maximum IS length with lowest blood flow needs in a porcine model by evaluating the physiological perfusion rates of different IS lengths. Blood flow in the SMA, aorta segment four, and general circulatory parameters were monitored before and after sequential intestinal resection. IS lengths of 30 cm, 60 cm, 120 cm, and 300 cm (n = 8 each) were compared. The IS blood flow requirements increased with IS length (30 cm: 19.5 ± 3.4 mL/min; 60 cm: 16.9 ± 6.7 mL/min; 120 cm: 34.9 ± 8.5 mL/min; 300 cm: 62.9 ± 11.6 mL/min). Absolute IS blood flow (P = .004), percentage IS blood flow uptake from the SMA (P = .001), and percentage IS blood flow uptake from the aorta (P = .005) increased significantly between 60 cm and 120 cm. We concluded that 60 cm was the maximum IS length before blood flow demands significantly increased in a porcine model.

The challenges of closing an ileostomy in patients with total intestinal aganglionosis after small bowel transplant.

We present the case of a 14-year-old male with a history of small bowel transplantation for long segment Hirschsprung's disease who underwent Duhamel ileorectal pull-through procedure. In post-transplant, the patient had no restrictions and was not TPN-dependent. To improve his quality of life, he and his family were interested in closing the ileostomy and undergoing pull-through surgery. The complexity of the case includes the presence of an aganglionic rectal segment-a short root of the mesentery due to the small bowel transplant-and significant immunosuppression. At the moment, he is continent, doing well, and has not had any remarkable complications.

A practical guide for small bowel transplantation in rats-review of techniques and models.

BACKGROUND: Animal models are a central aspect in research on small bowel transplantation (SBTx). Among them, rats are the preferred species because of their widespread availability and cost effectiveness. Because the complexity of the surgical procedure could per se influence the outcome of an experiment, a standardized and comparable technique is important. Based on of the vast amount of different models and surgical techniques published to this point, a review seemed necessary to guide investigators when choosing the suitable model. MATERIALS AND METHODS: A systematic literature search of original articles published between 1965 and 2016 using the Medline Database regarding techniques of SBTx in rats was conducted according to the Preferred reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles describing a new technique or evaluating different techniques were considered. RESULTS: A total of 38 publications fulfilled the selection criteria and were included. Data from these publications were regarded as too heterogeneous for statistical analysis. Depending on graft length and placement, full-length and reduced length heterotopic and orthotopic models were differentiated. Important factors concerning a good survival rate are the chosen model (heterotopic has a better outcome compared with orthotopic), a vascular flush of the graft in situ, a careful luminal flush of the graft, adequate fluid resuscitation, and a warm ischemia time of less than 40 min. CONCLUSIONS: SBTx in rats remains a complex and challenging procedure, which necessitates a standardized technique as well as sufficient training. By choosing the optimal experimental model, applying established strategies, and proven techniques, a standardized and scientifically reliable model can be achieved.

Autoantibodies to red blood cell antigens occur frequently with hemolysis among pediatric small bowel transplant recipients: clinical implications and management.

Reports have linked pediatric solid organ transplant recipients with the development of hemolytic autoimmune antibodies, especially in the setting of the immunosuppressant tacrolimus. This study aims to identify whether these observations also occurred at an institution that frequently performs pediatric multivisceral transplants and to characterize the treatment and outcome. Chart review was performed on all patients with RBC autoantibodies. Laboratory and clinical data were used to identify hemolysis. For transplant recipients with RBC autoantibodies, the type of transplant and outcome of the AIHA were profiled. One hundred twenty-eight patients were identified with RBC autoantibodies, of which 22 patients were solid organ transplant recipients, including 18 SB graft recipients. Sixteen of the 18 had evidence of hemolysis. The incidence rate of AIHA in this population is estimated to be 10%, resulting in significant cost. Treatment included immunosuppressant modulation, steroids, IVIG, and plasma exchange, with 12 of the 16 patients responding. RBC autoantibodies occur in up to 10% in pediatric SB transplant recipients, with high cost of obtaining compatible blood. Neither tacrolimus nor receipts of a donor spleen were associated with the development of AIHA. Treatment using steroids and IVIG appears to be effective.

Mesenchymal Stem Cell Extracellular Vesicles as a New Treatment Paradigm in Solid Abdominal Organ Transplantation: A Case Series.

Solid abdominal organ transplantation is fraught with variable rates of rejection and graft versus host disease (GVHD). We sought to determine the safety and efficacy of an advanced extracellular vesicle (EV) investigational product (IP) derived from mesenchymal stem cells (MSC) in the transplant patient population. Seven separate emergency investigational new drug (eNIDs) were filed with the Food and Drug Administration (FDA) for the emergency treatment of rejection of an isolated intestinal graft (n = 2), liver allograft graft (n = 2), modified multivisceral graft (n = 3), and GVHD in isolated intestinal transplant patients (n = 2). Fifteen milliliters of IP was administered intravenously on Day 0, 2, 4, and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to IP. All patients had improvement in clinical symptoms within 24 h, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation/rejection within 7 days of IP administration. Systemic use of a MSC-derived EV IP was successful in achieving histological clearance of intestinal, liver, and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD.

A metagenomic prospective cohort study on gut microbiome composition and clinical infection in small bowel transplantation.

Two-thirds of small-bowel transplantation (SBT) recipients develop bacteremia, with the majority of infections occurring within 3 months post-transplant. Sepsis-related mortality occurs in 31% of patients and is commonly caused by bacteria of gut origin, which are thought to translocate across the implanted organ. Serial post-transplant surveillance endoscopies provide an opportunity to study whether the composition of the ileal and colonic microbiota can predict the emergence as well as the pathogen of subsequent clinical infections in the SBT patient population. Five participants serially underwent aspiration of ileal and colonic bowel effluents at transplantation and during follow-up endoscopy either until death or for up to 3 months post-SBT. We performed whole-metagenome sequencing (WMS) of 40 bowel effluent samples and compared the results with clinical infection episodes. Microbiome composition was concordant between participants and timepoint-matched ileal and colonic samples. Four out of five (4/5) participants had clinically significant infections thought to be of gut origin. Bacterial translocation from the gut was observed in 3/5 patients with bacterial infectious etiologies. In all three cases, the pathogens had demonstrably colonized the gut between 1-10 days prior to invasive clinical infection. Recipients with better outcomes received donor grafts with higher alpha diversity. There was an increase in the number of antimicrobial resistance genes associated with longer hospital stay for all participants. This metagenomic study provides preliminary evidence to support the pathogen translocation hypothesis of gut-origin sepsis in the SBT cohort. Ileal and colonic microbiome compositions were concordant; therefore, fecal metagenomic analysis could be a useful surveillance tool for impeding infection with specific gut-residing pathogens.

Suppression of acute rejection by administration of prostaglandin E2 receptor subtype 4 agonist in rat organ transplantation models.

BACKGROUND: Prostaglandin E2 (PGE2) receptor subtype 4 (EP4) signaling is known to modulate the inflammation process. Several studies have demonstrated the potential utility of EP4-selective agonists for the management of autoimmune and inflammatory diseases. In the present study, we assessed the immunosuppressive efficacy of a selective EP4 agonist in experimental rat organ transplantation models. METHODS: We continuously injected a selective EP4 agonist (CAY10580) by subcutaneous insertion of infuser pumps into recipient rats that underwent heterotopic heart and small bowel transplantation. RESULTS: The administration of EP4 agonist significantly delayed cardiac allograft survival and delayed the onset of rejection in both the cardiac and intestinal allografts. Expression of proinflammatory cytokines of interferon-gamma was suppressed by the treatment compared with the vehicle-treated group. Furthermore, the expression of suppressor of cytokine signaling-1, a known intracellular regulation factor of IFN-gamma, was also down-regulated compared with the control group. CONCLUSIONS: These results suggest that selective EP4 agonists represent a novel class of immune-modulator drugs that could be useful for the management of acute allogeneic rejection.

Attenuation of rat chronic small bowel allograft rejection by n-3 polyunsaturated fatty acids is associated with reduced expression of graft IL-15.

Interleukin-15 was found to play key roles in various immunological processes including chronic rejection after renal and cardiac transplantation. n-3 polyunsaturated fatty acids (n-3 PUFA) have shown beneficial effects to chronic allograft rejection. The objective of this study is to search the possible mechanism of this inhibitory effect in chronic small bowel allograft rejection. Animals were divided into three groups: isograft (CsA + corn oil-supplemented diet); allograft (CsA + corn oil-supplemented diet); and allograft (CsA + fish oil-supplemented diet). Donor intestines from F344 rats were transplanted orthotopically into Lewis rat recipients. CsA was administered at 5 mg/kg/day for 2 wk post-operatively. Post-transplant weight was recorded. Histopathological changes and graft IL-15 expression were measured on POD 90. Chronic small bowel allograft rejection developed on POD 90. n-3 PUFA significantly decreased the score of chronic rejection and increased the post-operative weight gain rate. This attenuation is associated with reduced graft IL-15 expression. n-3 PUFA contributed to improved pathological and clinical outcome during chronic small bowel allograft rejection, and this improvement was associated with reduced graft IL-15 expression.

Bridging Liver Transplantation in the Treatment of Intestinal Failure Associated Liver Disease in Infants-A Bridge Too Far?

Infants with intestinal failure associated liver disease (IFALD) requiring liver and bowel transplant have a high mortality on the transplant waiting list due to the scarcity of the size-matched donor organs. Bridging liver transplantation has been used to allow the children to grow to a reasonable size so that a combined liver and small bowel transplant could be performed in the future. We report on two children with irreversible intestinal failure (ultra-short bowel syndrome secondary to gastroschisis and microvillous inclusion disease) with IFALD who underwent bridging liver transplantation at our institution. Both patients made a good recovery from their initial surgery. One patient died 6 months following surgery from generalized sepsis, and the other patient survived in good condition to undergo a combined liver and small bowel transplant but died a few days post-transplant. In the current era of scarcity of donor organs, this raises an ethical dilemma for the team involved regarding appropriate utilisation of a scarce resource.

Perioperative alterations in the intestinal microbiota and functional changes mediate innate immune activation after small bowel transplantation.

AIM: Small bowel transplantation (SBT) is the only therapy for end-stage short bowel syndrome. However, complicated pathological changes and an increased risk of postoperative infections in the perioperative period are major obstacles to patient survival, but the associated mechanisms remain unclear. METHODS: To explore perioperative alterations in the intestinal microbiota and their functional changes after SBT, 16S rRNA sequencing of ileostomy effluents and plasma analysis were performed pre-SBT and periodically post-SBT. RESULTS: The results suggested that the presence of Proteobacteria accelerated bacterial motility and chemotaxis during the first week in post-SBT recipients. Altered gut microbiota impaired intestinal barrier integrity and upregulated 16S rDNA, pathogen-associated molecular pattern (PAMP) and pattern-recognition molecule (PRM) levels in peripheral circulation. Importantly, the levels of neutrophils, monocytes, cytotoxic T lymphocytes, and natural killer cells and the expression of proinflammatory cytokines were increased in the peripheral blood and had potential roles in activating innate immune-mediated inflammatory injury after SBT. CONCLUSION: Together, our results suggest that altered microbiota and functional changes are probably related to innate immune-mediated inflammatory injury and graft survival after SBT, suggesting that the monitoring and regulation of intestinal microbiota are necessary for SBT patients.

A novel histidine-tryptophan-ketoglutarate formulation ameliorates intestinal injury in a cold storage and ex vivo warm oxygenated reperfusion model in rats.

AIM: The present study aims to evaluate protective effects of a novel histidine-tryptophan-ketoglutarate solution (HTK-N) and to investigate positive impacts of an additional luminal preservation route in cold storage-induced injury on rat small bowels. METHODS: Male Lewis rats were utilized as donors of small bowel grafts. Vascular or vascular plus luminal preservation were conducted with HTK or HTK-N and grafts were stored at 4°C for 8 h followed by ex vivo warm oxygenated reperfusion with Krebs-Henseleit buffer for 30 min. Afterwards, intestinal tissue and portal vein effluent samples were collected for evaluation of morphological alterations, mucosal permeability and graft vitality. RESULTS: The novel HTK-N decreased ultrastructural alterations but otherwise presented limited effect on protecting small bowel from ischemia-reperfusion injury in vascular route. However, the additional luminal preservation led to positive impacts on the integrity of intestinal mucosa and vitality of goblet cells. In addition, vascular plus luminal preservation route with HTK significantly protected the intestinal tissue from edema. CONCLUSION: HTK-N protected the intestinal mucosal structure and graft vitality as a luminal preservation solution. Additional luminal preservation route in cold storage was shown to be promising.

Small Bowel Transplantation.

Intestinal and multivisceral transplants are complex technical procedures that present unique challenges in the field of solid organ transplantation. This review aims to highlight the indications, techniques, outcomes, and complications specific to intestinal transplantation.

Living Donor Intestinal Transplantation.

Living donor intestinal transplantation (LDIT) has been improved leading to results comparable to those obtained with deceased donors. LDIT should be limited to specific indications and patient selection. The best indication is combined living donor intestinal/liver transplantation in pediatric recipients with intestinal and hepatic failure; the virtual elimination of waiting time may avoid the high mortality experienced by candidates on the deceased waiting list. Potentially, LDIT could be used in highly sensitized recipients to allow the application of de-sensitization protocols. In the case of available identical twins or HLA-identical sibling, LDIT has a significant immunologic advantage and should be offered.

Current treatment paradigms in pediatric short bowel syndrome.

Pediatric short bowel syndrome (SBS) is a serious condition which occurs in children with congenital or acquired reduction in length of the small intestine. SBS results in excessive fluid loss, nutrient malabsorption, electrolyte abnormalities, increased susceptibility to infections, parenteral nutrition associated complications and affects weight gain and growth. In children, SBS is debilitating and uniformly fatal without treatment. The primary goal of treatment is to restore enteral autonomy and reduce long-term dependence on parenteral support by increasing the absorptive potential of the remnant intestine. In this review, the medical and surgical management of SBS including pharmacologic agents, parenteral nutrition, dietary strategies, surgical lengthening procedures, and small bowel transplant will be discussed.