Growing experience of surgical gut rehabilitation: essential role in the management of gut failure in adult patients.

PURPOSE OF REVIEW: With the inherent therapeutic limitations of gut transplantation, the concept of surgical gut rehabilitation was introduced to restore nutritional autonomy in pediatric patients. With favorable outcomes in these young patients, there has been increasing interest in the applicability of gut rehabilitative surgery to a growing population of adults with gut failure due to various etiologies. We aim to review the current status of surgical gut rehabilitation for adult gut failure patients in the era of multidisciplinary gut rehabilitation and transplantation. RECENT FINDINGS: Indications for surgical gut rehabilitation have been gradually expanding, with gut failure after bariatric surgery recently added. Serial transverse enteroplasty (STEP) has been used with favorable outcomes in adult patients, including those with intrinsic intestinal disease. Autologous gut reconstruction (AGR) is the most frequently used surgical rehabilitative method; its outcome is further improved with conjunctive use of bowel lengthening and enterocyte growth factor as a part of comprehensive gut rehabilitation. SUMMARY: Accumulated experiences have validated the efficacy of gut rehabilitation for survival, nutritional autonomy, and quality of life in adults with gut failure of various etiology. Further progress is expected with growing experience around the world.

Blockade or deficiency of PD-L1 expression in intestinal allograft accelerates graft tissue injury in mice.

The importance of PD-1/PD-L1 interaction to alloimmune response is unknown in intestinal transplantation. We tested whether PD-L1 regulates allograft tissue injury in murine intestinal transplantation. PD-L1 expression was observed on the endothelium and immune cells in the intestinal allograft. Monoclonal antibody treatment against PD-L1 led to accelerated allograft tissue damage, characterized by severe cellular infiltrations, massive destruction of villi, and increased crypt apoptosis in the graft. Interestingly, PD-L1-/- allografts were more severely rejected than wild-type allografts, but the presence or absence of PD-L1 in recipients did not affect the degree of allograft injury. PD-L1-/- allografts showed increased infiltrating Ly6G+ and CD11b+ cells in lamina propria on day 4, whereas the degree of CD4+ or CD8+ T cell infiltration was comparable to wild-type allografts. Gene expression analysis revealed that PD-L1-/- allografts had increased mRNA expressions of Cxcr2, S100a8/9, Nox1, IL1rL1, IL1r2, and Nos2 in the lamina propria cells on day 4. Taken together, study results suggest that PD-L1 expression in the intestinal allograft, but not in the recipient, plays a critical role in mitigating allograft tissue damage in the early phase after transplantation. The PD-1/PD-L1 interaction may contribute to immune regulation of the intestinal allograft via the innate immune system.

Five Hundred Patients With Gut Malrotation: Thirty Years of Experience With the Introduction of a New Surgical Procedure.

OBJECTIVES: Define clinical spectrum and long-term outcomes of gut malrotation. With new insights, an innovative procedure was introduced and predictive models were established. METHODS: Over 30-years, 500 patients were managed at 2 institutions. Of these, 274 (55%) were children at time of diagnosis. At referral, 204 (41%) patients suffered midgut-loss and the remaining 296 (59%) had intact gut with a wide range of digestive symptoms. With midgut-loss, 189 (93%) patients underwent surgery with gut transplantation in 174 (92%) including 16 of 31 (16%) who had autologous gut reconstruction. Ladd's procedure was documented in 192 (38%) patients with recurrent or de novo volvulus in 41 (21%). For 80 patients with disabling gastrointestinal symptoms, gut malrotation correction (GMC) surgery "Kareem's procedure" was offered with completion of the 270° embryonic counterclockwise-rotation, reversal of vascular-inversion, and fixation of mesenteric-attachments. Concomitant colonic dysmotility was observed in 25 (31%) patients. RESULTS: The cumulative risk of midgut-loss increased with volvulus, prematurity, gastroschisis, and intestinal atresia whereas reduced with Ladd's and increasing age. Transplant cumulative survival was 63% at 10-years and 54% at 20-years with best outcome among infants and liver-containing allografts. Autologous gut reconstruction achieved 78% and GMC had 100% 10-year survival. Ladd's was associated with 21% recurrent/de novo volvulus and worsening (P > 0.05) of the preoperative National Institute of Health patient-reported outcomes measurement information system gastrointestinal symptom scales. GMC significantly (P ≤ 0.001) improved all of the symptomatology domains with no technical complications or development of volvulus. GMC improved quality of life with restored nutritional autonomy (P < 0.0001) and daily activities (P < 0.0001). CONCLUSIONS: Gut malrotation is a clinicopathologic syndrome affecting all ages. The introduced herein definitive correction procedure is safe, effective, and easy to perform. Accordingly, the current standard of care practice should be redefined in this orphan population.

Disease recurrence after gut transplantation.

PURPOSE OF REVIEW: Despite three decades of clinical experience, this article is the first to comprehensively address disease recurrence after gut transplantation. Pertinent scientific literature is reviewed and management strategies are discussed with new insights into advances in gut pathobiology and human genetics. RECENT FINDINGS: With growing experience and new perspectives in the field of gut transplantation, the topic of disease recurrence continues to evolve. The clinicopathologic spectrum and diagnostic criteria are better defined in milieu of the nature of the primary disease. In addition to neoplastic disorders, disease recurrence is suspected in patients with pretransplant Crohn's disease, gut dysmotility, hypercoagulability and metabolic syndrome. There has also been an increased awareness of the potential de-novo development of various disorders in the transplanted organs. For conventionally unresectable gastrointestinal and abdominal malignancies, ex-vivo excision and autotransplantation are advocated, particularly for the nonallotransplant candidates. SUMMARY: Similar to other solid organ and cell transplantations, disease recurrence has been suspected following gut transplantation. Despite current lack of conclusive diagnostic criteria, recurrence of certain mucosal and neuromuscular disorders has been recently described in a large single-centre series with an overall incidence of 7%. Disease recurrence was also observed in recipients with pretransplant hypercoagulability and morbid obesity with respective incidences of 4 and 24%. As expected, tumour recurrence is largely determined by type, extent and biologic behaviour of the primary neoplasm. With the exception of high-grade aggressive malignancy, disease recurrence is still of academic interest with no significant impact on overall short and long-term outcome.

Twenty Years of Gut Transplantation for Chronic Intestinal Pseudo-obstruction: Technical Innovation, Long-term Outcome, Quality of Life, and Disease Recurrence.

OBJECTIVE: To define long-term outcome, predictors of survival, and risk of disease recurrence after gut transplantation (GT) in patients with chronic intestinal pseudo-obstruction (CIPO). BACKGROUND: GT has been increasingly used to rescue patients with CIPO with end-stage disease and home parenteral nutrition (HPN)-associated complications. However, long-term outcome including quality of life and risk of disease recurrence has yet to be fully defined. METHODS: Fifty-five patients with CIPO, 23 (42%) children and 32 (58%) adults, underwent GT and were prospectively studied. All patients suffered gut failure, received HPN, and experienced life-threatening complications. The 55 patients received 62 allografts; 43 (67%) liver-free and 19 (33%) liver-contained with 7 (13%) retransplants. Hindgut reconstruction was adopted in 1993 and preservation of native spleen was introduced in 1999. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 41 (75%). RESULTS: Patient survival was 89% at 1 year and 69% at 5 years with respective graft survival of 87% and 56%. Retransplantation was successful in 86%. Adults experienced better patient (P = 0.23) and graft (P = 0.08) survival with lower incidence of post-transplant lymphoproliferative disorder (P = 0.09) and graft versus host disease (P = 0.002). Antilymphocyte pretreatment improved overall patient (P = 0.005) and graft (P = 0.069) survival. The initially restored nutritional autonomy was sustainable in 23 (70%) of 33 long-term survivors with improved quality of life. The remaining 10 recipients required reinstitution of HPN due to allograft enterectomy (n = 3) or gut dysfunction (n = 7). Disease recurrence was highly suspected in 4 (7%) recipients. CONCLUSIONS: GT is life-saving for patients with end-stage CIPO and HPN-associated complications. Long-term survival is achievable with better quality of life and low risk of disease recurrence.

Recurrence of Crohn's Disease After Small Bowel Transplantation: Fact or Fiction.

Small bowel transplant is an acceptable procedure for intractable Crohn's disease (CD). Some case reports and small series describe the apparent recurrence of CD in the transplanted bowel. This commentary discusses evidence in favor of and against this alleged recurrence and argues that a molecular characterization is needed to prove or disprove that inflammation emerging in the transplanted bowel is a true recurrence of the original CD.

Management of Five Hundred Patients With Gut Failure at a Single Center: Surgical Innovation Versus Transplantation With a Novel Predictive Model.

OBJECTIVE(S): To define the evolving role of integrative surgical management including transplantation for patients gut failure (GF). METHODS: A total of 500 patients with total parenteral nutrition-dependent catastrophic and chronic GF were referred for surgical intervention particularly transplantation and comprised the study population. With a mean age of 45 ±â€Š17 years, 477 (95%) were adults and 23 (5%) were children. Management strategy was guided by clinical status, splanchnic organ functions, anatomy of residual gut, and cause of GF. Surgery was performed in 462 (92%) patients and 38 (8%) continued medical treatment. Definitive autologous gut reconstruction (AGR) was achievable in 378 (82%), primary transplant in 42 (9%), and AGR followed by transplant in 42 (9%). The 84 transplant recipients received 94 allografts; 67 (71%) liver-free and 27 (29%) liver-contained. The 420 AGR patients received a total of 790 reconstructive and remodeling procedures including primary reconstruction, interposition alimentary-conduits, intestinal/colonic lengthening, and reductive/decompressive surgery. Glucagon-like peptide-2 was used in 17 patients. RESULTS: Overall patient survival was 86% at 1-year and 68% at 5-years with restored nutritional autonomy (RNA) in 63% and 78%, respectively. Surgery achieved a 5-year survival of 70% with 82% RNA. AGR achieved better long-term survival and transplantation better (P = 0.03) re-established nutritional autonomy. Both AGR and transplant were cost effective and quality of life better improved after AGR. A model to predict RNA after AGR was developed computing anatomy of reconstructed gut, total parenteral nutrition requirements, cause of GF, and serum bilirubin. CONCLUSIONS: Surgical integration is an effective management strategy for GF. Further progress is foreseen with the herein-described novel techniques and established RNA predictive model.

Chronic rejection after intestinal transplantation: A systematic review of experimental models.

Intestinal transplantation (ITX) constitutes a salvage treatment for irreversible intestinal failure and failure of parenteral nutrition. Chronic rejection (CR) remains the key obstacle for long-term intestinal graft survival but the pathomechanisms are incompletely understood. This study systematically reviews experimental models addressing CR after ITX in order to summarize current knowledge on CR pathogenesis and identify promising experimental strategies. A systematic literature search was conducted in line with the PRISMA guidelines, and 68 out of 677 articles qualified for the final analysis. The average methodological quality of the studies was suboptimal with 7 out of 11 points as assessed by a modified Oxford Centre for Evidence-Based Medicine score. Histology of the chronically rejected graft was almost universally integrated as outcome parameter but we found significant heterogeneity in utilized transplant techniques, organ preservation, immunosuppression and time points of CR-assessment. Several studies identified cellular and humoral immunologic mechanisms in chronic intestinal rejection. Yet, neither preventive nor therapeutic strategies against CR have been successfully introduced into human intestinal transplantation highlighting the persistent need for optimized experimental models. In this review, we aim to improve the translational value of forthcoming investigations on CR by discussing the experimental status quo and potential innovative approaches.

Evidence-Based Strategies and Recommendations for Preservation of Central Venous Access in Children.

Children with chronic illness often require prolonged or repeated venous access. They remain at high risk for venous catheter-related complications (high-risk patients), which largely derive from elective decisions during catheter insertion and continuing care. These complications result in progressive loss of the venous capital (patent and compliant venous pathways) necessary for delivery of life-preserving therapies. A nonstandardized, episodic, isolated approach to venous care in these high-need, high-cost patients is too often the norm, imposing a disproportionate burden on affected persons and escalating costs. This state-of-the-art review identifies known failure points in the current systems of venous care, details the elements of an individualized plan of care, and emphasizes a patient-centered, multidisciplinary, collaborative, and evidence-based approach to care in these vulnerable populations. These guidelines are intended to enable every practitioner in every practice to deliver better care and better outcomes to these patients through awareness of critical issues, anticipatory attention to meaningful components of care, and appropriate consultation or referral when necessary.

Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome.

The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs.

Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome.

The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs.

Total pancreaticoduodenectomy with autologous islet transplantation 14 years after liver-contained composite visceral transplantation.

Chronic pancreatitis (CP) is a severely disabling disorder with potential detrimental effects on quality of life, gut function, and glucose homeostasis. Disease progression often results in irreversible morphological and functional abnormalities with development of chronic pain, mechanical obstruction, and pancreatic insufficiency. Along with comprehensive medical management, the concept of total pancreatectomy and islet autotransplantation (TP-AIT) was introduced 40 years ago for patients with intractable pain and preserved beta-cell function. With anticipated technical difficulties, total excision of the inflamed-disfigured gland is expected to alleviate the incapacitating visceral pain and correct other associated abdominal pathology. With retrieval of sufficient islet-cell mass, the autologous transplant procedure has the potential to maintain an euglycemic state without exogenous insulin requirement. The reported herein case of CP-induced recalcitrant pain and foregut obstruction is exceptional because of the technical challenges in performing native pancreaticoduodenectomy in close proximity to the composite visceral allograft with complex vascular and gut reconstructions. Equally novel is transplanting the auto-islets in the liver-contained visceral allograft. Despite intravenous nutrition shortly after birth, liver transplantation at age 13, retransplantation with liver-contained visceral allograft at age 17 and TP-AIT at age 31, the 38-year-old recipient is currently pain free with full nutritional autonomy and normal glucose homeostasis.

Imaging of Intestinal and Multivisceral Transplantation.

Intestinal transplantation has evolved from its experimental origins in the mid-20th century to its status today as an established treatment option for patients with end-stage intestinal failure who cannot be sustained with total parenteral nutrition. The most common source of intestinal failure in both adults and children is short-bowel syndrome, but a host of other disease processes can lead to this common end-point. The development of intestinal transplantation has presented multiple hurdles for the transplant community, including technical challenges, immunologic pitfalls, and infectious complications. Despite these hurdles, the success rate has climbed over the past decades owing to achievements that include improved surgical techniques, new immunosuppressive regimens, and more effective strategies for posttransplant surveillance and management. Nearly 2800 intestinal transplants have been performed worldwide, and current patient and graft survival rates are now comparable to those of other types of solid organ transplantations. As their population continues to increase, it will be increasingly likely that intestinal-transplant patients will seek imaging at sites other than transplant centers. Therefore, it is important that diagnostic and interventional radiologists be familiar with the procedure, its common variations, and the spectrum of postoperative complications. In this article, the authors provide an overview of intestinal transplantation, including the indications, variations, expected postoperative anatomy, and range of potential complications. ©RSNA, 2018.

Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients.

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid-derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33+ CD11b+ lineage(CD3/CD56/CD19)- HLA-DR-/low cells with 3 subsets, CD14- CD15- (e-MDSCs), CD14+ CD15- (M-MDSCs), and CD14- CD15+ (PMN-MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M-MDSC numbers were maintained at a high level after 2 months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)-6 levels and the glucocorticoid administration index. IL-6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M-MDSCs and e-MDSCs expressed CCR1, -2, and -3; e-MDSCs and PMN-MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45+ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor-reactive T cell-mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR.

Lipid metabolism and functional assessment of discarded human livers with steatosis undergoing 24 hours of normothermic machine perfusion.

Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD.