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.

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.

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.

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.

Autologous Reconstruction and Visceral Transplantation for Management of Patients With Gut Failure After Bariatric Surgery: 20 Years of Experience.

OBJECTIVE: Bariatric surgery (BS) is currently the most effective treatment for severe obesity. However, these weight loss procedures may result in the development of gut failure (GF) with the need for total parenteral nutrition (TPN). This retrospective study is the first to address the anatomic and functional spectrum of BS-associated GF with innovative surgical modalities to restore gut function. METHODS: Over 2 decades, 1500 adults with GF were referred with history of BS in 142 (9%). Of these, 131 (92%) were evaluated and received multidisciplinary care. GF was due to catastrophic gut loss (Type-I, 42%), technical complications (Type-II, 33%), and dysfunctional syndromes (Type-III, 25%). Primary bariatric procedures were malabsorptive (5%), restrictive (19%), and combined (76%). TPN duration ranged from 2 to 252 months. RESULTS: Restorative surgery was performed in 116 (89%) patients with utilization of visceral transplantation as a rescue therapy in 23 (20%). With a total of 317 surgical procedures, 198 (62%) were autologous reconstructions; 88 (44%) foregut, 100 (51%) midgut, and 10 (5%) hindgut. An interposition alimentary conduit was used in 7 (6%) patients. Reversal of BS was indicated in 84 (72%) and intestinal lengthening was required in 10 (9%). Cumulative patient survival was 96% at 1 year, 84% at 5 years, and 72% at 15 years. Nutritional autonomy was restored in 83% of current survivors with persistence or relapse of obesity in 23%. CONCLUSIONS: GF is a rare but serious life-threatening complication after BS. Successful outcome is achievable with comprehensive management, including reconstructive surgery and visceral transplantation.

Combined surgical and interventional radiologic management strategies in patients with arterial pseudo-aneurysms after multivisceral transplantation.

BACKGROUND: Multivisceral transplantation has recently evolved to be a life-saving procedure for patients with intestinal failure and complex abdominal pathology. A composite aortic graft is always needed to restore the arterial flow to the transplanted organs. Accordingly, arterial complications can be life-threatening requiring prompt intervention. Herein, we describe innovative technical approaches in seven recipients who developed pseudo-aneurysm (PA) after transplantation. METHODS: With a total of 285 composite visceral transplants, 15 (5.2%) patients experienced vascular complications. Of these, 7 were life-threatening PAs that were diagnosed 61 to 2677 days after transplantation. Due to the anatomic and technical complexity of the allograft vasculature, endovascular techniques were introduced alone (n=2) or in conjunction with surgical intervention (n=5) in an attempt to rescue patients and salvage the transplanted organs. RESULTS: The endovascular and surgical technical approaches used for each of the 7 PA actively bleeding patients was successful in 5 (71%). Of these, 2 (40%) are alive 86 to 117 months after the intervention. The remaining 5 recipients died of recurrent hemorrhage (n=2), liver failure (n=1), and pneumonia (n=1). The cause of death was unknown in the remaining patient. Retransplantation and intra-abdominal infections were major risk factors. Candida was the most common isolated microorganism. CONCLUSIONS: Recipients of composite visceral allografts are at risk of developing life-threatening PAs, particularly in those with early posttransplantation abdominal infections. Prompt multidisciplinary diagnosis and therapeutic approaches are crucial management strategies.

Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: a pilot study.

BACKGROUND: Bortezomib, a proteasome inhibitor used to treat multiple myeloma, has been administered (± plasma exchange ± intravenous immunoglobulin [IVIg]) in attempts to reduce antibodies against human leukocyte antigens (HLA) in sensitized patients undergoing organ transplantation. To our knowledge, bortezomib has not been investigated for its effect on natural anti-pig antibodies. If bortezomib could reduce the production of anti-pig antibodies, this would likely be beneficial to the outcome of pig organ grafts in primates. METHODS: Nine patients received bortezomib either to reduce anti-HLA antibody levels before organ allotransplantation or to treat antibody-mediated rejection. Patients at the Mayo Clinic (Group 1; n = 4) received bortezomib alone, whereas at the UPMC (Group 2; n = 5), this was combined with plasmaphereses ± IVIg in some cases. Anti-pig IgM and IgG levels against wild-type (WT) and α1,3-galactosyltransferase gene knockout (GTKO) pig aortic endothelial cells (flow cytometry-relative mean fluorescence intensity) and anti-Gal IgM and IgG (ELISA-OD480 nm ) were measured pre- and post-bortezomib therapy. RESULTS: Mean anti-pig IgM levels were 11.2 (WT) and 1.9 (GTKO) pre-bortezomib treatment and 9.4 (WT: P = 0.02) and 1.7 (GTKO: P = 0.33) post-bortezomib treatment, respectively. Mean anti-pig IgG levels were 4.3 (WT) and 1.5 (GTKO) pre-bortezomib treatment and 3.6 (WT: P = 0.21) and 1.4 (GTKO: P = 0.20) post-bortezomib treatment, respectively. Mean anti-Gal IgM and IgG levels were 0.7 and 1.1, respectively, pre-treatment, and 0.6 (P = 0.03) and 1.1 (NS), respectively, post-treatment. When the data were analyzed in Groups 1 and 2 separately, there were no significant differences between the pre- and post-bortezomib levels of anti-pig, anti-non-Gal, or anti-Gal IgM or IgG. CONCLUSIONS: From this limited study, we conclude that bortezomib might reduce anti-Gal IgM levels in primates, but, in this respect alone, is unlikely to have any significant effect on the outcome of GTKO pig organ transplantation.

Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation.

OBJECTIVE: To assess long-term survival, graft function, and health-related quality of life (QOL) after visceral transplantation. BACKGROUND: Despite continual improvement in early survival, the long-term therapeutic efficacy of visceral transplantation has yet to be defined. METHODS: A prospective cross-sectional study was performed on 227 visceral allograft recipients who survived beyond the 5-year milestone. Clinical data were used to assess outcome including graft function and long-term survival predictors. The socioeconomic milestones and QOL measures were assessed by clinical evaluation, professional consultation, and validated QOL inventory. RESULTS: Of 376 recipients, 227 survived beyond 5 years, with conditional survival of 75% at 10 years and 61% at 15 years. With a mean follow-up of 10 ± 4 years, 177 (92 adults, 85 children) are alive, with 118 (67%) recipients 18 years or older. Nonfunctional social support and noninclusion of the liver in the visceral allograft are the most significant survival risk factors. Nutritional autonomy was achievable in 160 (90%) survivors, with current serum albumin level of 3.7 ± 0.5 gm/dL and body mass index of 25 ± 6 kg/m(2). Despite coexistence or development of neuropsychiatric disorders, most survivors were reintegrated to society with self-sustained socioeconomic status. In parallel, most of the psychological, emotional, and social QOL measures significantly (P < 0.05) improved after transplantation. Current morbidities with potential impact on global health included dysmotility (59%), hypertension (37%), osteoporosis (22%), and diabetes (11%), with significantly (P < 0.05) higher incidence among adult recipients. CONCLUSIONS: With new tactics to further improve long-term survival including social support measures, visceral transplantation has achieved excellent nutritional autonomy and good QOL.

A decade of experience with a single dose of rabbit antithymocyte globulin or alemtuzumab pretreatment for intestinal and multivisceral transplantation.

In 2001, we hypothesized that recipient pretreatment with a single-dose of an anti-lymphoid depleting agent followed by tacrolimus monotherapy could promote alloengraftment with minimal long-term immunosuppression. As of November 2010, the protocol was applied to 175 adults: 46 (26%) received rATG (5 mg/kg) and 129 (74%) received alemtuzumab (30 mg). Targeted 12-hour tacrolimus trough levels were 10-15 ng/mL followed by attempts of spaced-dose reduction in selected patients. Steroids were limited to recipients with serum sickness, adrenal insufficiency, and rejection. With a 13% re-transplantation rate, overall 1-, 5-, and 10-year survival was 93%, 70%, and 50% for patients with respective graft survival of 86%, 57%, and 48%. Rejection and infection continued to be leading causes of graft loss. With better patient (p = 0.04) and graft (p = 0.03) survival among alemtuzumab-pretreated patients, cumulative risk of end-stage acute/chronic rejection was similar (p = 0.4) between both antibody cohorts. Tacrolimus spaced-dose reduction was sustainable in 56% of current survivors with 40% of the total population continuing to be steroid-free. However, few of these recipients experienced life-threatening infections and de-novo malignancy. Despite an increase in long-term survival and achievement of partial 'prope' tolerance reported herein, innovative immunosuppressive strategies along with availability of reliable tolerance assays are still required to further improve long-term visceral allograft acceptance.

Pancreaticobiliary complications after composite visceral transplantation: incidence, risk, and management strategies.

BACKGROUND: Combined liver/small-bowel (L/SB) and multivisceral (MV) transplantation has been increasingly used with significant improvement in outcome. OBJECTIVE: To report our experience with pancreaticobiliary (PB) complications in this unique population. DESIGN AND SETTING: Single-center cohort study using a prospectively completed database. PATIENTS AND INTERVENTIONS: From May 1990 to November 2008, records of 271 consecutive patients who received 289 composite visceral grafts were retrospectively reviewed; 151 of the allografts were L/SB (52%) and the remaining 138 were MV. MAIN OUTCOME MEASUREMENTS: Type, incidence, risk factors, clinical features, and management of PB complications. RESULTS: PB complications were diagnosed in 44 patients with an incidence of 16%. Biliary complications developed in 20 patients (ampullary stenosis in 9, bile duct casts/stones in 6, and bile duct leaks in 5), pancreatic complications occurred in 19 patients (necrotizing pancreatitis in 7, edematous pancreatitis in 6, and pancreatic duct fistulae in 6), and combined biliary and pancreatic complications occurred in 5 patients. The risk of PB complications was significantly higher in MV graft recipients compared with L/SB recipients with a rate of 25% compared with 9%, respectively. ERCP was instrumental in the diagnosis and/or treatment of ampullary stenosis, bile duct casts and stones, bile duct leaks, and recurrent acute pancreatitis. Combined endoscopic and surgical intervention was required in most cases of pancreatic duct fistulae. Surgical intervention was performed in patients with pancreatic allograft necrosis and complex anastomotic biliary leaks. LIMITATIONS: Single-center study. CONCLUSIONS: PB complications are common after composite visceral transplantation. Awareness of these complications is important to the transplantation team to ensure early diagnosis and appropriate intervention in an attempt to minimize morbidity and mortality.

Modified multivisceral transplantation with spleen-preserving pancreaticoduodenectomy for patients with familial adenomatous polyposis "Gardner's Syndrome".

BACKGROUND: Liver-sparing "modified" multivisceral transplantation (MMVTx) has recently been more used for patients with diffuse gastrointestinal disorders and preserved hepatic functions. Evisceration techniques with preservation of native spleen were also introduced to reduce risk of posttransplant lymphoproliferative disorders. This study focuses on the indications of MMVTx for patients with familial adenomatous polyposis (FAP) and the technical feasibility of performing spleen-preserving pancreaticoduodenectomy (SPPD). METHODS: Between 1993 and 2009, 10 FAP patients required MMVTx. Nine were adults and one was a child, with a female:male ratio of 1:1. RESULTS: Short gut with duodenal adenomatosis and extensive desmoid tumors with pancreaticoduodenal involvement dictated need for MMVTx. SPPD was technically feasible in four recipients, and conventional evisceration including splenectomy was performed in remaining six recipients. With an overall cumulative survival of 90% at 1 year and 77% at 10 years, all SPPD recipients were alive with no single example of posttransplant lymphoproliferative disorder, graft-versus-host disease, or chronic rejection. However, SPPD was associated with an increase (P>0.3) in total ischemia time, operative time, and packed red blood cells requirement but with shorter (P=0.6) length of hospital stay. With a mean follow-up of 50±45 months (range 18-128 months), none of the 10 recipients experienced intraabdominal desmoid tumor recurrence or developed de novo visceral allograft neoplasm. CONCLUSION: MMVTx is a valuable therapeutic option for FAP patients who are in need for visceral transplantation with pathologic involvement of the pancreaticoduodenal complex. SPPD is technically feasible, and efforts should always be made to preserve native spleen because of the reported herein therapeutic advantages.

Modified "liver-sparing" multivisceral transplant with preserved native spleen, pancreas, and duodenum: technique and long-term outcome.

BACKGROUND: Modification of the originally described multivisceral transplant operation was introduced at our institution 17 years ago. Donor liver was spared, and native spleen along with pancreaticoduodenal complex was preserved. METHODS: Thirty-six modified multivisceral grafts that include stomach, duodenum, pancreas, and intestine were given to 30 adults and six children. Leading causes of intestinal failure were pseudo-obstruction and Gardner's syndrome. Native spleen was preserved in 24 (67%) recipients along with pancreaticoduodenal complex in 18 (50%). Immunosuppression was tacrolimus-based, and recipient preconditioning was utilized in 80% of patients. RESULTS: Patient survival was 94% at 1 year and 75% at 5 years with graft survival of 91% and 51%; respectively. With mean follow-up of 51 ± 35 months, full nutritional autonomy was achieved in 89% of current survivors with no single example of disease recurrence. Preservation of native spleen was associated with increased survival and reduced risk of PTLD, life-threatening infections, and GVHD with no significant impact on graft loss due to rejection. Concomitant preservation of pancreaticoduodenal complex eliminated risks of biliary complications and glucose intolerance. CONCLUSION: Modified multivisceral transplantation with and without preservation of native spleen, pancreas, and duodenum is a valid therapeutic option for patients with diffuse gastrointestinal disorders and preserved hepatic functions.

Surgical shunt versus TIPS for treatment of variceal hemorrhage in the current era of liver and multivisceral transplantation.

Over the last 3 decades, management of acute variceal bleeding and measures to prevent recurrent episodes has evolved due to the introduction of new therapeutic modalities including innovative surgical and minimally invasive shunt procedures. Such an evolution has been compounded by the parallel progress that has been achieved in organ transplantation. This article focuses primarily on the commonly used surgical and radiologic shunt procedures. Liver and multivisceral transplantation are also briefly discussed as important parts of the algorithmic management of these complex patients, particularly those with hepatic decompensation and portomesenteric venous thrombosis.

Elevated myeloid: plasmacytoid dendritic cell ratio associates with early acute cellular rejection in pediatric small bowel transplantation.

BACKGROUND: Acute cellular rejection affects more than 60% of children after small bowel transplantation (SBTx). Dendritic cells (DCs) are potent antigen-presenting cells, modulate immune responses to gut microbes, and may serve as markers of rejection-prone small bowel transplantation (SBTx). METHODS: Myeloid CD11c DC (MDC), which may have inflammatory functions, and plasmacytoid CD123 DC (PDC), which may have tolerogenic potential, were measured by flow cytometric analysis, longitudinally (pretransplant, and at days 1 to 60, 61 to 200 posttransplant) in 23 children after SBTx. All children received cadaveric allografts with rabbit anti-human thymocyte globulin induction and steroid-free tacrolimus maintenance therapy. Rejectors were those children (n=16), who experienced biopsy-proven acute cellular rejection within 60 days of SBTx. RESULTS: Of 69 maximum possible observations, 62 were available for analysis. Among rejectors, a significantly higher MDC:PDC ratio (P=0.004) was associated with numerically higher MDC counts and significantly lower PDC frequencies (P=0.017) during the 1- to 60-day time period, compared with nonrejectors. Logistic regression analysis, leave-one-out cross-validation, and receiver operating characteristic analysis revealed that MDC:PDC ratio more than or equal to 1.52 was associated with rejector status with sensitivity/specificity of 86/67% during the 1- to 60-day risk period for early SBTx rejection. Repeated measures analysis showed a significantly higher MDC:PDC ratio (P=0.043, F-test) among rejectors, compared with nonrejectors in cumulative data for pre-SBTx and 1- to 60-day time points. No correlation was seen between DC subsets and tacrolimus blood concentration at any time point. CONCLUSIONS: We conclude that an elevated MDC:PDC ratio associates with early small bowel allograft rejection and may, therefore, identify at-risk recipients in the clinic.

The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation.

BACKGROUND: Intestinal transplantation has evolved into an effective therapy for patients with intestinal failure and the inability to be maintained on total parenteral nutrition. Long-term heavy immunosuppression and complex systemic disturbances increase the risk of the neurologic complications. METHODS: This retrospective analysis identified the post-transplant neurologic complications in adult patients who underwent intestinal transplantation at the University of Pittsburgh Medical Center between May 1990 and August 1998. The recipients received 28 isolated intestine, 17 composite liver-intestine, and nine multivisceral allografts. RESULTS: With a median follow-up of 25 months, 46 of 54 recipients (68%) developed headaches (n = 27; 50%), encephalopathy (n = 23; 43%), seizures (n = 9; 17%), neuromuscular disorders (n = 4; 7%), opportunistic CNS infections (n = 4; 7%), and ischemic stroke (n = 2; 4%). CONCLUSIONS: Under high maintenance immunosuppression, intestinal transplant recipients were at high risk for neurologic complications. Future studies are needed to describe post-transplant neurologic complications with modern immunosuppression protocols.

Lymphoproliferative disorders and de novo malignancies in intestinal and multivisceral recipients: improved outcomes with new outlooks.

BACKGROUND: Early experience with intestinal and multivisceral transplantation was plagued with high risk of rejection and posttransplant lymphoproliferative disorders (PTLD). To improve outcome, innovative management and immunosuppressant strategies were sequentially evolved. METHODS: With initiation of the program in 1990, serial monitoring of Epstein-Barr-Viral load was introduced in 1994 with adoption of preemptive antiviral therapy. In 1995, cyclophosphamide or daclizumab induction was added to the tacrolimus-steroid-based multiple drug immunosuppressions. Such a conventional approach was replaced in 2001 with a novel immunosuppressive protocol consisting of recipient pretreatment with a single dose of rabbit antithymocyte globulin or alemtuzumab and posttransplant tacrolimus monotherapy. RESULTS: With a total of 395 consecutive primary recipients, de novo malignancy(s) developed in 61 (15%) patients, with PTLD in 52 (13%), and nonlymphoid cancer (NLC) in 13 (3.2%). Malignancy was donor driven in 3 (4.6%) recipients and associated with graft-versus-host disease in 7 (11.4%). Children were at a significantly higher risk (P<0.001) of PTLD, and adults were more vulnerable (P=0.01) to NLC. With multivariate analyses, type of immunosuppression, recipient age, splenectomy, and treatment of rejection were significant PTLD risk factors. CONCLUSIONS: Despite pretransplant lymphoid depletion, preemptive antiviral therapy and minimization of posttransplant immunosuppression significantly reduced PTLD morbidity (P=0.0001) and mortality (P=0.001) with no impact on NLC. Patient survival was also improved (P=0.0001) with 91% at 1 year and 75% at 5 years.