Indications for Intestinal Transplantation.

Outcomes for patients with chronic intestinal failure have improved with organization of experts into multidisciplinary teams delivering care in intestinal rehabilitation programs. There have been improvements in understanding of intestinal failure complications as well as development of newer therapies that have amplified the improvements in survival. In spite of this encouraging trend, patients who fail PN are often referred too late for intestinal transplantation. The author proposes a more rational framework that might allow earlier identification of intestinal failure patients at risk for PN-failure, who could appropriately be considered earlier for intestinal transplantation with improvements in overall outcomes.

Risk factors for renal dysfunction after isolated intestinal transplantation.

INTRODUCTION: Kidney dysfunction is a known complication of intestinal transplantation; however, the rate of development and risk factors for chronic kidney disease (CKD) remain poorly defined. METHODS: This was a single-center retrospective review of isolated adult intestinal allograft recipients from 2011 to 2019. Patients who died or experienced graft loss within 1-year or had a prior transplant were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation at 0-, 6- and 12-months post-transplant, and multivariable linear regression was performed to identify variables associated with adjusted eGFR at 1-year. Independent variables included age, ethnicity, BMI, history of diabetes/hypertension, vasopressor use, TPN and stoma days, urinary or bloodstream infections, intravenous contrast exposure, rejection, concomitant immunosuppression, and time above the therapeutic range of tacrolimus. Variables with a p < .1 in univariate analysis were considered for multivariable modeling. RESULTS: Thirty-three patients were included with a mean age of 43.9 ± 13.0. A mean 42.3% decline in eGFR was observed at 1-year post-transplant, with 15.2% of patients developing new stage 4/5 CKD. Factors associated with a greater decline in adjusted eGFR in the univariate model included increasing age, decreased BMI, stoma days, and vasopressor use. In the adjusted multivariable model patient age (ß = -.77, p < .01) and stoma days (ß = -.06, p < .01) remained significant. Tacrolimus and sirolimus exposure were not associated with decline in eGFR at 1 year. CONCLUSIONS: Renal dysfunction is common following intestinal transplantation. The need for stoma creation should be carefully considered, and reversal should be performed when feasible for renal protection.

Characteristics of chronic intestinal failure in the USA based on analysis of claims data.

BACKGROUND: This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization. METHODS: Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history. RESULTS: Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition. CONCLUSIONS: Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents.

Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.

Evaluation of the fibrosis-4 index for detection of advanced fibrosis among individuals at risk for intestinal failure-associated liver disease.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) refers to the spectrum of liver injury secondary to IF and parenteral nutrition use. Our aim was to evaluate the use of noninvasive indices of liver fibrosis to detect advanced fibrosis among individuals at risk for IFALD. METHODS: We performed a secondary analysis of a retrospective study, including all liver biopsies performed on individuals undergoing intestinal transplantation (ITx) between January 2000 and May 2014. To determine the clinical utility of detecting advanced fibrosis, receiver operating characteristic curves were developed. Comparison between the area under the curves was performed by DeLong test. RESULTS: Fifty-three patients had a liver biopsy performed at the time of ITx; 13 of 53 (24.5%) patients had advanced fibrosis. The fibrosis-4 (FIB-4) index positively correlated to the stage of fibrosis on liver biopsy (r = 0.426, P = .002). When compared against the FIB-4 index, the aspartate aminotransferase to platelet ratio index had a significantly decreased ability to correctly identify the presence of advanced fibrosis (P = .019). When determining the cutoff value with 90% specificity for the detection of advanced fibrosis, a FIB-4 index of ≥4.4 had a sensitivity of 0.462 and a positive predictive value of 0.6. CONCLUSION: In this retrospective cohort study, we found a positive correlation between the FIB-4 index and the liver fibrosis stage as characterized by the Brunt classification. This evaluation of the FIB-4 index against liver biopsies supports the use of the FIB-4 index in the detection of liver fibrosis in IF.

Impact of the acuity circle model for liver allocation on multivisceral transplant candidates.

Liver allocation was updated on February 4, 2020, replacing a Donor Service Area (DSA) with acuity circles (AC). The impact on waitlist outcomes for patients listed for combined liver-intestine transplantation (multivisceral transplantation [MVT]) remains unknown. The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify all candidates listed for both liver and intestine between January 1, 2018 and March 5, 2021. Two eras were defined: pre-AC (2018-2020) and post-AC (2020-2021). Outcomes included 90-day waitlist mortality and transplant probability. A total of 127 adult and 104 pediatric MVT listings were identified. In adults, the 90-day waitlist mortality was not statistically significantly different, but transplant probability was lower post-AC. After risk-adjustment, post-AC was associated with a higher albeit not statistically significantly different mortality hazard (sub-distribution hazard ratio[sHR]: 8.45, 95% CI: 0.96-74.05; p = .054), but a significantly lower transplant probability (sHR: 0.33, 95% CI: 0.15-0.75; p = .008). For pediatric patients, waitlist mortality and transplant probability were similar between eras. The proportion of patients who underwent transplant with exception points was lower post-AC both in adult (44% to 9%; p = .04) and pediatric recipients (65% to 15%; p = .002). A lower transplant probability observed in adults listed for MVT may ultimately result in increased waitlist mortality. Efforts should be taken to ensure equitable organ allocation in this vulnerable patient population.

Knowledge of chronic intestinal failure among US gastroenterologists: Cause for concern and learning opportunity.

BACKGROUND: Chronic intestinal failure (CIF) is an ultrarare disease, with an estimated national prevalence of ∼25,000 cases. There is a suspicion of widespread lack of expertise in CIF care, but no formal assessment tool or data exist. We developed and validated a knowledge test in CIF and now report our preliminary results from testing CIF knowledge in a cohort of US gastroenterologists. METHOD: We developed a 20-question knowledge test in CIF, covering four key components of IF. After internal testing, refinement, and revision, we administered the test to a convenience sample of experts and nonexperts in IF. We then deployed the validated test to a cohort of 100 US gastroenterologists. RESULTS: The test had a Cronbach alpha of 0.74, suggesting a reliable test, with a threshold score to discriminate experts and nonexperts of 13.4 (maximum 20) and with a sensitivity of 81.3% and specificity of 86.4%. The overall mean score of 8.2 for the 100 US gastroenterologists was at the level of nonexperts in our convenience sample. CONCLUSION: The preliminary results of our validated knowledge test in IF among a broad group of US gastroenterologists demonstrate lack of knowledge in IF.

Left lateral segment pediatric liver transplantation: a 25 year experience at Mount Sinai.

BACKGROUND: Outcomes of left lateral segment (LLS) grafts in pediatric recipients were compared between living (LD-LLS) and deceased donor (DD-LLS) grafts. METHODS: 195 LLS grafts (99DD-LLS-96LD-LLS) were analyzed with a median follow-up of 9.1years. The primary endpoints were overall patient/graft survival. RESULTS: LD-LLS grafts were younger (0.9vs.1.4years, p = 0.039), more likely to have a fulminant liver failure (17.9%vs.5.3%,p = 0.002), less likely to have a metabolic disorder (6.3%vs.25.5%,p = 0.002), and less likely to be undergoing retransplantation (5.3% vs.16.2%,p = 0.015). There was a trend toward decreased hepatic artery thrombosis in LD-LLS grafts (6.6% vs. 15.5%,p = 0.054). No differences in the overall biliary complications occurred. The LD-LLS group had prolonged survival compared to the DD-LLS group with 10-year survival rates of 81%, and 74% (p = 0.005), respectively. LD-LLS grafts had longer graft survival compared to DD-LLS grafts (10-year graft survival 85%vs.67%,p = 0.005). Recipient age >1year (HR 2.39,p = 0.026), aortic reconstruction (HR 2.12,p = 0.046) and vascular complication (HR 3.12,p < 0.001) were independent predictors of poor patient survival. Non-biliary liver disease (HR 2.17,p = 0.015), DD-LLS (HR 2.06,p = 0.034) and vascular complication (HR 4.61,p < 0.001) were independent predictors of poor graft survival. CONCLUSION: The use of SLT remains a viable option with excellent long-term outcomes. We show improved graft and patient survival with living donor grafts.

Learn Intestinal Failure Tele-ECHO Project: An innovative online telementoring and case-based learning clinic.

Intestinal failure (IF) is a rare chronic disease requiring intravenous (IV) fluids or parenteral nutrition (PN) dependency for optimal patient health and sustenance. The complex care is best managed by specialized multidisciplinary teams. Patients who have limited access to intestinal rehabilitation centers often receive IV/PN care from clinicians lacking specialty expertise. An innovative videoconferencing project was launched in May 2019 to provide online telementoring and case-based learning in IF. The Extension for Community Healthcare Outcomes (ECHO) model was adopted to provide education and virtual support via the Learn Intestinal Failure Tele-ECHO (LIFT-ECHO) project. Online clinics include patient case presentations, moderated discussion, best-practice recommendations, and didactic continuing education lectures on IF- and PN-related topics. Participation is interprofessional and international. Via knowledge dissemination and specialty mentorship, LIFT-ECHO is expected to improve healthcare for patients with IF and transform care delivery by overcoming the limitations in access to expertise.

Tacrolimus time-in-therapeutic range is associated with freedom from acute rejection and graft failure following intestinal transplantation.

BACKGROUND: Trough-adjusted tacrolimus is commonly prescribed following intestinal transplantation to prevent allograft rejection. Despite established practice, there remains limited direct evidence linking tacrolimus levels with improved clinical outcomes. METHODS: This was a single-center review of all adult non-liver containing intestinal allograft recipients from 2011 to 2018. Patients received lymphocyte depleting induction and maintenance immunosuppression consisting of tacrolimus and a corticosteroid taper. Tacrolimus time-in-therapeutic range (TAC-TTR) was calculated for all patients from the date of transplant until 1-year post-transplant using Rosendaal's method. Cox-Proportional hazards modeling was utilized to assess freedom from acute rejection and graft failure stratified by TAC-TTR quartile. RESULTS: 47 patients were included in the review. Mean TAC-TTR for the cohort was 30.2% ± 11.4. Fifteen episodes of acute rejection were observed, 8 of which were severe. Patients in the highest TAC-TTR quartile >36% had a lower incidence of acute rejection and graft failure relative to patients with a TAC-TTR <20%. Cox-Proportional hazards modeling found a 10% decrease in TAC-TTR was associated with an increased hazard for acute rejection (2.03), severe acute rejection (2.19), and graft loss (3.33). CONCLUSION: The results of this study suggest that decreasing TAC-TTR is a risk factor for both acute rejection as well as intestinal allograft failure.

Disseminating Knowledge in Intestinal Failure: Initial Report of the Learn Intestinal Failure Tele-ECHO (LIFT-ECHO) Project.

BACKGROUND: Intestinal failure (IF) is defined as an ultrarare disease, with an estimated prevalence of ∼25,000 cases in the US. There is a suspicion of disparities in outcomes in IF care, likely related to widespread lack of expertise. The Extension for Community Healthcare Outcomes (ECHO) model originally described by Dr Sanjeev Arora has been used to disseminate knowledge and best practices in many chronic diseases to improve outcomes. We examined our initial experience with using the ECHO model to disseminate learning in IF. METHOD: This is a retrospective review of the launch, growth, and geographic reach of the Learn Intestinal Failure TeleECHO (LIFT-ECHO) program using prospectively collected data. RESULTS: The LIFT-ECHO program has achieved significant geographic reach and clinician engagement. The program has reached close to two-thirds of the states in the US and several countries outside. Clinician engagement in the learning program appears to be growing exponentially. CONCLUSION: It is feasible to use the ECHO model to disseminate knowledge in managing a rare disease like IF while maintaining fidelity to the proven model. Studies are underway to demonstrate direct benefit to patients.

Enhanced virtual crossmatch in intestinal transplantation: association with outcomes and application in practice.

Background: The presence of preformed donor-specific antibodies in recipient serum against anti-human leukocyte antigen is a significant risk factor that negatively affects the outcomes of intestinal transplantation. Avoiding high-risk intestinal transplantation by physical and virtual cross matches has had limited success due to time constraints and ineffective correlation, respectively. Methods: We developed a guideline to improve the association between physical and virtual cross matches using the retrospective data of 56 consecutive primary adult isolated intestinal transplantations from a single center. Results: The mean fluorescence intensity of 2,000 for positive donor-specific antibodies revealed the best association between physical and virtual cross matches among different cut-off values, but with an unacceptable false positive rate of 54%. An enhanced virtual cross match with the summation of the mean fluorescence intensity of each anti-human leukocyte antigen improved the association between physical and virtual cross matches, with a sensitivity of 83% and specificity of 98%. Conclusions: This enhanced virtual cross match more effectively predicts high-risk intestinal transplantation and is a better substitute for physical cross-match than the current virtual cross match. It also helps to avoid ill-considered abandonment of intestinal transplantation that is unnecessarily deemed high risk based on a simple virtual cross match.

The role of endoscopy in the small intestinal transplant recipient: A review.

Intestinal transplantation (ITx) is the treatment of choice for patients with intestinal failure who have developed life-threatening complications related to long-term parenteral nutrition. Patients may also undergo ITx as part of a combined liver-intestine or multivisceral transplant for a variety of indications, most commonly intestinal failure-associated liver disease or porto-mesenteric thrombosis. Endoscopy plays a critical role in the posttransplant management of these patients, most commonly in the diagnosis and management of rejection, which occurs in up to 30-40% of patients within the first-year posttransplant. With a lack of noninvasive biomarkers to identify the presence of rejection, endoscopy and biopsy remain the gold standard for its diagnosis. Endoscopic evaluation of the graft is also important in the identification of other complications post-ITx, including posttransplant lymphoproliferative disorder, graft-versus-host disease, and enteric infections. Each patient's posttransplant anatomy may be slightly different, making endoscopy sometimes technically challenging and necessitating clear and frequent communication with the surgical team in order to help identify the highest yield approach. Herein, we review the most common pathologies found endoscopically in the post-ITx patient and describe some of the unique challenges the endoscopist faces when evaluating these complex patients.

"Stoma or no stoma": First report of intestinal transplantation without stoma.

Recent data suggest that frequent endoscopy and biopsy without evidence of graft dysfunction does not appear to confer survival advantage after intestinal transplantation. After abandoning protocol surveillance, endoscopic examination was decreased significantly at our center. These observations led us to question the need for stoma creation in intestinal transplantation. Herein, we report clinical outcomes of intestinal transplantation without stoma, compared to conventional transplant with stoma. Data analysis was limited to adult intestinal transplantation without liver allograft between 2015 and 2018. We compared patient and graft survival, frequency of endoscopic evaluation, episodes of acute rejection, nutritional therapy, and renal function between "Control group (with stoma)," n = 18 grafts in 16 patients and "Study group (without stoma)," n = 16 grafts in 15 patients. Overall outcome was similar between the 2 groups with respect to graft and patient survival, episodes of acute rejection, and its response to treatment. Nutritional outcomes were similar in both groups. Fewer antidiarrheal medications were required in the study group, but this did not translate into demonstrable gains in preservation of renal function, despite an apparent trend to improvement. Intestinal transplantation without stoma appears to be an acceptable practice model without obvious adverse impact on outcome.

Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials.

BACKGROUND: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome-associated intestinal failure (SBS-IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. METHODS: Safety data from four prospective clinical trials of teduglutide in patients with SBS-IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. RESULTS: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS-IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. CONCLUSIONS: Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. CLINICAL TRIAL REGISTRY INFORMATION: NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65.

Adult intestinal transplantation in the United States.

PURPOSE OF REVIEW: There has been a striking decline in the annual volumes of adult intestinal transplants performed in the United States from a peak in 2008, reaching its lowest volume in 2019. The current review examines the pattern and potential reasons for the decline. RECENT FINDINGS: We observe that while improvements in intestinal rehabilitation may be contributing to some of the decline, movements of key personnel and the paucity of experts in a rarefied field may also be contributing to declining volumes. SUMMARY: We suggest that the decline in volumes of adult intestinal transplants are likely to be multifactorial. At a time of improving transplant outcomes, the indications for intestinal transplant suggested by the Centers for Medicare and Medicaid Services, may be outdated and worthy of revision.

Nontransplant Surgery for Intestinal Failure.

Insufficient absorptive mucosal surface is the fundamental problem in the short bowel state. Intestinal adaptation has been well studied, and it is well recognized that it may lead to dilatation of the bowel with increased thickness of the bowel wall, resulting from both mucosal hypertrophy and hyperplasia. Autologous reconstructive surgery exploits bowel dilatation in short bowel syndrome and maximizes the absorptive potential of the available mucosal surface. Indeed, autologous gastrointestinal reconstructive procedures may be better viewed as optimizing bowel diameter rather than focusing on length, thus allowing better prograde peristalsis and improved contact between luminal nutrients and mucosa, ultimately enhancing absorption.

Routine surveillance endoscopy and biopsy after isolated intestinal transplantation-Revisiting the gold standard.

The value of endoscopy and biopsy after intestinal transplantation in the absence of clinical concerns has never been investigated. We examined clinical yield of routine surveillance endoscopy and biopsy (control group, n = 28, Jan 2011 to Jun 2014). Most episodes of acute rejection were diagnosed when there were clinical symptoms or signs such as increased stoma output, fever, or bacteremia, but not by routine surveillance endoscopy and biopsy. The new protocol abandoned routine surveillance. Intestinal allografts were examined only when relevant clinical symptoms and/or signs raised concern for graft dysfunction. We compared outcomes between control and study groups (new protocol, n = 25, Jul 2014 to Dec 2016). Incidence of acute rejection (32% vs 32%), graft salvage rate after acute rejection treatment (78% vs 63%), patient survival (75% vs 88% 1 year, 71% vs 83% 3 years after intestinal transplantation), and graft survival (68% vs 80% 1 year, 61% vs 76% 3 years after intestinal transplantation) were similar between control and study groups. Protocol-driven, routine surveillance endoscopy, and biopsy do not appear to confer any survival advantage to patients or grafts. Endoscopy and biopsy "for cause" without routine surveillance seem to be effective and adequate to monitor intestinal allografts.

Is There a Role for Desensitization in Intestinal Transplantation?

Human leukocyte antigen allosensitization prior to transplant can increase the risk of early graft loss and prolong waitlist times for intestinal transplant candidates. Desensitization offers a potential therapeutic option to reduce the quantity of preformed antibodies prior to organ allocation and facilitate transplantation with a more immunologically compatible donor allograft. However, there remains a paucity of data to guide the use of desensitization in the setting of intestinal transplantation. As a result, in this review we evaluate the existing literature supporting the role of desensitization therapy in intestinal transplant, describe our own experience with the implementation of a risk-stratified desensitization protocol, and finally explore barriers and unanswered questions that continue to limit the widespread adoption of desensitization as a management strategy for highly sensitized intestinal transplant candidates.