Evaluation of pediatric patients for intestinal transplantation in the modern era.

OBJECTIVES: To review recent evaluations of pediatric patients with intestinal failure (IF) for intestinal transplantation (ITx), waiting list decisions, and outcomes of patients listed and not listed for ITx at our center. METHODS: Retrospective chart review of 97 patients evaluated for ITx from January 2014 to December 2021 including data from referring institutions and protocol laboratory testing, body imaging, endoscopy, and liver biopsy in selected cases. Survival analysis used Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Patients were referred almost entirely from outside institutions, one-third because of intestinal failure-associated liver disease (IFALD), two-thirds because of repeated infective and non-IFALD complications under minimally successful intestinal rehabilitation, and a single patient because of lost central vein access. The majority had short bowel syndrome (SBS). Waiting list placement was offered to 67 (69%) patients, 40 of whom for IFALD. The IFALD group was generally younger and more likely to have SBS, have received more parenteral nutrition, have demonstrated more evidence of chronic inflammation and have inferior kidney function compared to those offered ITx for non-IFALD complications and those not listed. ITx was performed in 53 patients. Superior postevaluation survival was independently associated with higher serum creatinine (hazard ratio [HR] 15.410, p = 014), whereas inferior postevaluation survival was associated with ITx (HR 0.515, p = 0.035) and higher serum fibrinogen (HR 0.994, p = 0.005). CONCLUSIONS: Despite recent improvements in IF management, IFALD remains a prominent reason for ITx referral. Complications of IF inherent to ITx candidacy influence postevaluation and post-ITx survival.

Suppressor T helper type 17 cell responses in intestinal transplant recipients with allograft rejection.

BACKGROUND: Intestinal transplant (ITx) rejection is associated with memory T helper type 17 cell (Th17) infiltration of grafted tissues. Modulation of Th17 effector cell response is facilitated by T regulatory (Treg) cells, but a phenotypic characterization of this process is lacking in the context of allograft rejection. METHODS: Flow cytometry was performed to examine the expression of surface receptors, cytokines, and transcription factors in Th17 and Treg cells in ITx control (n = 34) and rejection patients (n = 23). To elucidate key pathways guiding the rejection biology, we utilized RNA sequencing (RNAseq) and assessed epigenetic stability through pyrosequencing of the Treg-specific demethylated region (TSDR). RESULTS: We found that intestinal allograft rejection is characterized by Treg cellular infiltrates, which are polarized toward Th17-type chemokine receptor, ROR-γt transcription factor expression, and cytokine production. These Treg cell subsets have maintained epigenetic stability, as defined by FoxP3-TSDR methylation status, but displayed upregulation of functional Treg and purinergic signaling genes by RNAseq analysis such as CD39, in keeping with suppressor Th17 properties. CONCLUSION: We show that ITx rejection is associated with increased polarized cells that express a Th17-like phenotype concurrent with regulatory purinergic markers.

Idiopathic Ileal Ulceration After Intestinal Transplantation.

Background: Idiopathic ileal ulceration after intestinal transplantation (ITx) has been discussed infrequently and has an uncertain natural history and relation to graft rejection. Herein, we review our experience with this pathology. Methods: We retrospectively reviewed 225 ITx in 217 patients with minimum 1 y graft survival. Routine graft endoscopy was conducted up to twice weekly within the first 90 d after ITx, gradually decreasing to once yearly. Risks for ulceration over time were evaluated using Cox regression. Results: Of 93 (41%) patients with ulcers, 50 were found within 90 d after ITx mostly via ileoscopy; delayed healing after biopsy appeared causal in the majority. Of the remaining 43 patients with ulcers found >90 d after ITx, 36 were after ileostomy closure. Multivariable modeling demonstrated within 90-d ulcer associations with increasing patient age (hazard ratio [HR], 1.027; P < 0.001) and loop ileostomy (versus Santulli ileostomy; HR, 0.271; P < 0.001). For ulcers appearing after ileostomy closure, their sole association was with absence of graft colon (HR, 7.232; P < 0.001). For ulcers requiring extended anti-microbial and anti-inflammatory therapy, associations included de novo donor-specific antibodies (HR, 3.222; P < 0.007) and nucleotide oligomerization domain mutations (HR, 2.772; P < 0.016). Whole-cohort post-ITx ulceration was not associated with either graft rejection (P = 0.161) or graft failure (P = 0.410). Conclusions: Idiopathic ulceration after ITx is relatively common but has little independent influence on outcome; risks include ileostomy construction, colon-free ITx, immunologic mutation, and donor sensitization.

Techniques for Closing the Abdominal Wall in Intestinal and Multivisceral Transplantation: A Systematic Review.

Short bowel syndrome is the most common etiology of intestinal failure, resulting from either resections of different intestinal segments or a congenital condition. Due to the absence or considerable reduction of intestinal loops in the abdominal cavity, patients with short bowel syndrome present with atrophy and muscle retraction of the abdominal wall, which leads to loss of abdominal domain and elasticity. This complication is an aggravating factor of intestinal transplantation since it can prevent the primary closure of the abdominal wall. A vast array of surgical techniques to overcome the challenges of the complexity of the abdominal wall have been described in the literature. The aim of our study was to review the modalities of abdominal wall closure in intestinal/multivisceral transplantation. Our study consisted of a systematic review following the methodological instructions described in the PRISMA guidelines. Duplicate studies and studies that did not meet the criteria for the systematic review were excluded, especially those without relevance and an explicit relationship with the investigated theme. After this step, 63 articles were included in our study. The results obtained with these techniques have been encouraging, but a high incidence of wound complications in some reports has raised concerns. There is no consensus among transplantation centers regarding which technique would be ideal and with higher success rates and lower rates of complications.

Graft Versus Host Disease After Intestinal Transplantation: A Single-center Experience.

BACKGROUND: Graft versus host disease (GVHD) is an uncommon but highly morbid complication of intestinal transplantation (ITx). In this study, we reviewed our 17-y experience with GVHD focusing on factors predicting GVHD occurrence and survival. METHODS: Retrospective review of 271 patients who received 1 or more ITx since program inception in 2003 with survival analysis using Cox proportional hazard modeling. RESULTS: Of 271 patients, 28 developed GHVD 34 (18-66) d after ITx presenting with rash or rash with fever in 26, rectosigmoid disease in 1, and hemolysis in 1; other sites, mainly rectosigmoid colon, were involved in 13. Initial skin biopsy demonstrated classic findings in 6, compatible findings in 14, and no abnormalities in 2. Additional sites of GVHD later emerged in 14. Of the 28 patients, 16 died largely from sepsis, the only independent hazard for death (hazard ratio [HR], 37.4181; P = 0.0008). Significant (P < 0.0500) independent hazards for occurrence of GVHD in adults were pre-ITx functional intestinal failure (IF) (HR, 15.2448) and non-IF diagnosis (HR, 20.9952) and early post-ITx sirolimus therapy (HR, 0.0956); independent hazards in children were non-IF diagnosis (HR, 4.3990), retransplantation (HR, 4.6401), donor:recipient age ratio (HR, 7.3190), and graft colon omission (HR, 0.1886). Variant transplant operation was not an independent GVHD hazard. CONCLUSIONS: Initial diagnosis of GVHD after ITx remains largely clinical, supported but not often confirmed by skin biopsy. Although GVHD risk is mainly recipient-driven, changes in donor selection and immunosuppression practice may reduce incidence and improve survival.

Type 3 innate lymphoid cells are associated with a successful intestinal transplant.

Although innate lymphoid cells (ILCs) play fundamental roles in mucosal barrier functionality and tissue homeostasis, ILC-related mechanisms underlying intestinal barrier function, homeostatic regulation, and graft rejection in intestinal transplantation (ITx) patients have yet to be thoroughly defined. We found protective type 3 NKp44+ ILCs (ILC3s) to be significantly diminished in newly transplanted allografts, compared to allografts at 6 months, whereas proinflammatory type 1 NKp44- ILCs (ILC1s) were higher. Moreover, serial immunomonitoring revealed that in healthy allografts, protective ILC3s repopulate by 2-4 weeks postoperatively, but in rejecting allografts they remain diminished. Intracellular cytokine staining confirmed that NKp44+ ILC3 produced protective interleukin-22 (IL-22), whereas ILC1s produced proinflammatory interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Our findings about the paucity of protective ILC3s immediately following transplant and their repopulation in healthy allografts during the first month following transplant were confirmed by RNA-sequencing analyses of serial ITx biopsies. Overall, our findings show that ILCs may play a key role in regulating ITx graft homeostasis and could serve as sentinels for early recognition of allograft rejection and be targets for future therapies.

Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab.

Intestinal transplantation (ITx) can be life-saving for patients with advanced intestinal failure experiencing complications of parenteral nutrition. New surgical techniques and conventional immunosuppression have enabled some success, but outcomes post-ITx remain disappointing. Refractory cellular immune responses, immunosuppression-linked infections, and posttransplant malignancies have precluded widespread ITx application. To shed light on the dynamics of ITx allograft rejection and treatment resistance, peripheral blood samples and intestinal allograft biopsies from 51 ITx patients with severe rejection, alongside 37 stable controls, were analyzed using immunohistochemistry, polychromatic flow cytometry, and reverse transcription-PCR. Our findings inform both immunomonitoring and treatment. In terms of immunomonitoring, we found that while ITx rejection is associated with proinflammatory and activated effector memory T cells in the blood, evidence of treatment efficacy can only be found in the allograft itself, meaning that blood-based monitoring may be insufficient. In terms of treatment, we found that the prominence of intra-graft memory TNF-α and IL-17 double-positive T helper type 17 (Th17) cells is a leading feature of refractory rejection. Anti-TNF-α therapies appear to provide novel and safer treatment strategies for refractory ITx rejection; with responses in 14 of 14 patients. Clinical protocols targeting TNF-α, IL-17, and Th17 warrant further testing.

CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation.

Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (TRM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (TEM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+TRM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+TRM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+TRM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in TEM at the time of GvHD, possibly of donor derivation; (2) donor TRM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.

Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children.

OBJECTIVES: Intestinal transplantation is an option for permanent intestinal failure with parenteral nutrition intolerance. We sought to determine long-term intestinal graft survival in pediatric patients at our center and to identify factors influencing survival. METHODS: Retrospective chart review of 86 patients transplanted between 2003 and 2013, targeting potential explanatory variables related to demographics, perioperative factors, and postoperative complications. RESULTS: Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively. Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure compared with 45% with functional intestinal failure (P = 0.0055). Compared with nonsurvival, 5-year graft survival was also associated with reduced incidences of graft-versus-host disease (2% vs 16%, P = 0.0237), post-transplant lymphoproliferative disorder (3% vs 24%, P = 0.0067), and de novo donor-specific antibodies (19% vs 57%, P = 0.0451) plus a lower donor-recipient weight ratio (median 0.727 vs 0.923, P = 0.0316). Factors not associated with 5-year intestinal graft survival included graft rejection of any severity and inclusion of a liver graft. Factors associated with graft survival at 10 years were similar to those at 5 years. CONCLUSIONS: In our experience, outcomes in pediatric intestinal transplantation have improved substantially for anatomic but not functional intestinal failure. Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit. Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.

Donor-specific antibody management in intestine transplantation: hope for improving the long-term durability of the intestine allograft?

PURPOSE OF REVIEW: In this review, we appraise the current status of donor-specific antibody (DSA) monitoring and treatment in the literature and highlight the current challenges in DSA management for the intestine transplant community. RECENT FINDINGS: Sensitizing events are common in patients referred for intestinal transplant, as these patients universally are repeatedly exposed to immune activation and inflammatory events. Both preformed and de novo DSA have been shown to increase rejection and graft loss in intestine recipients. Avoidance of preformed DSA with the use of virtual crossmatch (VXM) and antibody monitoring protocols to detect and treat de novo DSA may improve intestine transplant outcomes. There is no consensus on the clinical and pathologic criteria that are required to diagnose antibody-mediated rejection (AMR) in the intestine recipient. Therefore, many clinicians treat AMR based on the coincidence of DSA and acute biopsy-proven rejection. Inclusion of the liver in the intestine allograft appears to be immunologically protective in the setting of DSA with improved outcomes and a higher rate of preformed DSA clearance. Critically, DSA has been linked to chronic rejection and poor long-term outcomes in the intestine recipient. SUMMARY: On the basis of increasing evidence in the intestine transplant literature, it appears that avoidance of preformed DSA and aggressive monitoring and treatment of de novo DSA is a key to long-term survival following intestine transplantation.

Adult Intestinal Transplantation.

Adult intestinal transplantation differs significantly from pediatric intestinal transplantation. While indications have remained largely consistent since 2000, indications for adults have expanded over the last two decades to include motility disorders and desmoid tumors. Graft type in adult recipients depends on the distinct anatomic characteristics of the adult recipient. Colonic inclusion, while initially speculated to portend unfavorable outcomes due to complex host-bacterial interactions has increased over the past two decades with superior graft survival and improved patient quality of life. Overall, outcomes have steadily improved. For adult intestinal transplant candidates, intestinal transplantation remains a mainstay therapy for complicated intestinal failure and is a promising option for other life threatening and debilitating conditions.

Impact of early reoperation on graft survival after liver transplantation: Univariate and multivariate analysis.

BACKGROUND: Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited. STUDY DESIGN: Single-center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival. RESULTS: Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358-19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048). CONCLUSIONS: This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies.

World's smallest combined en bloc liver-pancreas transplantation.

We present a case of a 2-year-old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin-dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children.

Advances in allograft monitoring after intestinal transplantation.

PURPOSE OF REVIEW: The intestinal allograft, with an enormous lymphoid load, is a highly immunogenic organ which elicits a strong alloimmune response. In the early posttransplant period, a robust graft biopsy protocol via a temporary ileostomy is utilized for surveillance to detect rejection. In the later posttransplant period, after enteral continuity is reestablished, graft biopsies via a colonoscopy become more cumbersome. Alternative methods for intestinal allograft monitoring other than graft biopsy are of particular interest. RECENT FINDINGS: Biomarkers and diagnostic tools, such as granzyme B, perforin, fecal calprotectin, citrulline, donor-specific antibody, and zoom video endoscopy have all been studied for application as reliable methods of performing intestinal allograft surveillance. Each modality has the capability to monitor a separate and unique process in the host-allograft immune response. SUMMARY: The goal to find a reliable, reproducible, and noninvasive method for intestinal graft monitoring remains an elusive one. Many of the current modalities available only serve to act as complementary tests in conjunction with astute clinical observations. Graft biopsy remains the gold standard for monitoring the intestinal allograft.

Chronic mucosal inflammation/inflammatory bowel disease-like inflammation after intestinal transplantation: where are we now?

PURPOSE OF REVIEW: The purpose of this review is to highlight the similarities between inflammatory bowel disease and the state of the intestine allograft after transplantation. RECENT FINDINGS: The mutant nucleotide-binding oligomerization protein 2 (NOD2) gene, which encodes for an intracellular protein that serves as an innate immune system microbial sensor in macrophages, dendritic cells, and certain intestinal epithelial cells, has been recognized as a risk factor in Crohn's disease. Similarly, recent studies have also highlighted the contribution the NOD2 mutation may have on intestinal failure itself. More specifically, in intestinal transplant recipients with the NOD2 mutation, the discovery of the reduced ability to prevent bacterial clearance, increased enterocyte stress response, and failure of key downstream expression of important cytokines and growth factors have been implicated as major factors in intestinal transplant outcomes, namely graft loss and septic death. Treatment strategies with anti tumor necrosis factor (TNF) α, similar to inflammatory bowel disease, have been employed in intestinal transplantation with promising results. SUMMARY: In intestinal transplantation, there is evidence that the classical alloimmunity pathways that lead toward graft dysfunction and eventual graft loss may, in fact, be working in concert with a disordered innate immune system to produce a state of chronic inflammation not unlike that seen in inflammatory bowel disease.

Modified multivisceral transplantation with splenopancreatic preservation.

A common requirement of multivisceral transplantation has been removal of the native duodenum, pancreas and spleen in the process of abdominal exenteration. Oftentimes, though, the indication for their removal has not been underlying disease states in those organs. In order to avoid adverse sequelae of pancreas and splenic removal for purely anatomic reasons, we have designed a new approach and have performed a multivisceral transplantation with splenopancreatic preservation. In this modified multivisceral technique, the native spleen and pancreas are preserved with venous outflow through a native portocaval shunt, and native pancreatic exocrine drainage is established to the donor jejunum. Risk of transplant pancreatic insufficiency, posttransplant lymphoproliferative disorder, and postsplenectomy sepsis may be avoided utilizing this technique. This new modification of multivisceral transplantation allows pancreaticosplenic preservation while facilitating stomach replacement for those patients requiring intestinal replacement therapy. It represents another step towards minimizing morbidities associated with these lifesaving transplants.

Intestinal replacement therapy: timing and indications for referral of patients to an intestinal rehabilitation and transplant program.

Current treatment options for patients suffering from intestinal insufficiency include all forms of intestinal replacement therapy (IRT). Parenteral nutrition has achieved extended success for the majority of patients requiring interval treatment, however, complications leading to failure of this treatment increases with the duration of therapy. There is currently no consensus as to the appropriate timing for transplantation of the intestine or the timing of referral for evaluation at a center experienced with this therapy. Certain patient characteristics warrant evaluation. Those patients with no jejunoileum who have guaranteed lifelong parenteral dependence, both adult and pediatric, should be immediately referred to a transplant center due to the high likelihood of the development of liver disease. Patients with metastatic infectious complications from catheter sepsis, patients with cholestasis seen intermittently with sepsis episodes, patients who are not successfully weaning and who demonstrate progressive thrombocytopenia, and patients with motility disorder experiencing deterioration should also warrant early referral to an intestinal rehabilitation and transplant program. The objective of evaluation is to maximize the opportunities for rehabilitation while not missing the critical window of opportunity for successful transplantation when needed. We favor an aggressive directed approach to rehabilitation, coupled with psychological preparation for both transplantations and other options. Early referral requires trust between the patient, referring physician, and the transplant team to assure that a rush to judgment will not lead to a premature transplant. The current wait list mortality is high, mandating early referral and listing with an approach aimed at maximizing both the success of gastrointestinal support, as well as of transplantation when necessary.